TWI831855B - Novel indazole compounds or salts thereof - Google Patents

Abstract

An indazole compound represented by the following general formula (I) or a salt thereof: [In the formula, X, R ₁ , R ₂ , ring A, L ₁ , L ₂ , L ₃ and R ₅ are as described in this specification].

Description

Novel indazole compounds or salts thereof

[Cross-reference of related applications] The claims of this application are based on Japanese Patent Application No. 2018-202226, filed on October 26, 2018, and Japanese Patent Application No. 2019-075118, filed on April 10, 2019 (the entire disclosure of these incorporated by reference into this specification). The present invention relates to an indazole compound or a salt thereof which has inhibitory activity against the G12C mutation of KRAS, and a pharmaceutical composition containing the same as an active ingredient.

RAS is a low-molecular GTP-binding protein with a molecular weight of approximately 21 kDa and functions as a molecular switch (on off switch). RAS can bind to GTP by binding to guanine nucleotide exchange factor (GEF) proteins (e.g., SOS1) that promote the release of bound nucleotides, thereby releasing GDP. Once RAS binds to GTP, it will become activated (on), allowing C-Raf and PI3 kinase to assemble and activate proteins necessary for the transmission of messages from other receptors. In addition, RAS has an enzyme activity that cleaves the terminal phosphate group of the nucleotide and converts it into GDP. However, its conversion speed is usually slow, and it can be greatly accelerated by proteins that are GTPase-activating proteins (GAP) (for example, RasGAP). . Once GTP is converted to GDP, RAS becomes inactive (off).

The main known subfamilies of RAS are HRAS, KRAS and NRAS. Among them, KRAS mutations have been observed in many malignant tumors, and mutations have been observed in 95% of pancreatic cancers, 45% of colorectal cancers, and 35% of lung cancers. Many of these mutations occur at the 12th glycine residue. Especially in lung adenocarcinoma, about 90% of all mutations occur at the 12th glycine residue. And it is reported that the largest number of mutations (44%) is to cysteine (Non-patent Document 1).

In recent years, reports have pointed out that ARS-853 binds to the cysteine of the G12C mutation of the inactive (GDP) KRAS, preventing the conversion to the active (GTP) form, blocking downstream messages, and further inhibiting the G12C mutation of KRAS. of cancer cells induce cell death (Patent Document 1, Non-Patent Document 2). In addition, there are reports that ARS-1620 with a quinazoline skeleton can obtain anti-tumor effects in cancer-bearing mice with G12C mutations in KRAS by improving the metabolic stability of ARS-853 mice (Patent Document 2, Non-Patent Document 3).

[Advanced technical documents] [Patent Document] Patent Document 1: International Publication No. W0 2014/152588 Patent Document 2: International Publication No. W0 2015/054572

[Non-patent literature] Non-patent document 1: Nature Reviews Drug Discovery 13(11),828-51,2014 Non-patent literature 2: Cancer Discov.6(3),316-29,2016 Non-patent literature 3: Cell. 172(3),578-89,2018

Summary of the invention [Problem to be solved by the invention] The object of the present invention is to provide a novel compound or salt thereof that binds to mutant cysteine of KRAS and blocks downstream signaling, and a pharmaceutical composition containing the same.

[Means used to solve problems] The inventors of the present case have conducted intensive research to solve the aforementioned problems, and found that the compound group represented by the following formula (I) having an indazole and a heteroaryl group strongly binds to the G12C mutated cysteine of KRAS, preventing function of KRAS, and then complete the present invention. That is, the present invention provides the following [1] to [43]. [1] An indazole compound or a salt thereof, represented by the following general formula (I):

[Chemical formula 1]

[In the _formula , A C2-C6 alkenyl group, a C2-C6 alkynyl group which may also have a substituent, a C3-C10 cycloalkyl group which may also have a substituent, a C6~C10 aromatic hydrocarbon group, a 4~10-membered saturated heterocyclic group, or Unsaturated heterocyclic group with 5 to 10 members; R ₂ represents a hydrogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, C1-C6 alkyl group which may also have a substituent, and C2- which may also have a substituent. C6 alkenyl, C2-C6 alkynyl which may also have a substituent, C3-C10 cycloalkyl which may also have a substituent, C6~C10 aromatic hydrocarbon group, 4~10 membered saturated heterocyclic group or 5~10 Member's unsaturated heterocyclic group; L ₁ represents -NH-C(Ra) ₂ -, (in the formula, Ra is the same or different, representing a hydrogen atom, a deuterium atom or a C1-C6 alkyl group); Ring A can also represent A 5-membered unsaturated heterocyclic group with a substituent; one of A1, A2 and A3 is a nitrogen atom or a sulfur atom that may also have a substituent, and the remaining A1, A2 and A3 are the same or different , represents a carbon atom that may have a substituent, a nitrogen atom, a sulfur atom or an oxygen atom that may have a substituent; when A1 is a carbon atom with a substituent or a nitrogen atom that has a substituent, the substituent represents: selected from It consists of a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a C1-C6 alkyl group of Rb, a C2-C6 alkenyl group of Rb, or a C2- of Rb. C6 alkynyl group may also have a C3-C10 cycloalkyl group of Rc, may also have a C4-C10 cycloalkenyl group of Rc, may also have an aromatic hydrocarbon group of C6~C10 of Rc, may also have 4~10 members of Rc At least one of the group consisting of a saturated heterocyclic group and an unsaturated heterocyclic group that may also have 5 to 10 members of Rc, (Rb represents a halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, C1 -C6 alkoxy group, C1-C6 alkylamino group, C3-C6 cycloalkyl group, C6-C10 aromatic hydrocarbon group which may also have a substituent, or a 4 to 10-membered saturated heterocyclic group which may also have a substituent , Rc represents halogen atom, cyano group, nitro group, amine group, hydroxyl group, carboxyl group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group , C1-C6 alkylamino, C1-C6 alkylcarbonyl, C1-C6 alkoxy-C1-C6 alkyl, C7-C20 aralkyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl , C6-C10 aromatic hydrocarbon group, 4 to 10-membered saturated heterocyclic group or 5 to 10-membered unsaturated heterocyclic group, when there are multiple Rb, the plurality of Rb may be the same or different, and there are multiple Rc when A2 is a carbon atom with a substituent or a nitrogen atom with a substituent, the substituent represents: selected from: hydrogen atom, halogen atom, cyano group , nitro group, amino group, hydroxyl group, carboxyl group, a C1-C6 alkyl group which may also have a substituent, a C2-C6 alkenyl group which may also have a substituent, and a C2-C6 alkynyl group which may also have a substituent. At least one of them; When A3 is a carbon atom with a substituent or a nitrogen atom with a substituent, the substituent represents: selected from the group consisting of hydrogen atom, halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, At least one of the group consisting of a C1-C6 alkyl group which may also have a substituent, a C2-C6 alkenyl group which may also have a substituent, and a C2-C6 alkynyl group which may also have a substituent; L ₂ represents:

[Chemical formula 2]

(In the formula,

[Chemical formula 3]

Represents a saturated heterocyclic group with 4 to 8 members, in which N represents a nitrogen atom, and may also have 1 or 2 heteroatoms selected from sulfur atoms and oxygen atoms, with at least 1 nitrogen atom, and R ₃ represents a hydrogen atom or C1-C6 alkyl group, R ₄ represents halogen atom, cyano group, nitro group, amine group, hydroxyl group, carboxyl group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, R When there are multiple R _4s , the multiple R _4s may be the same or different. When the same carbon atom is replaced by 2 R _4s and the 2 R _4s are C1-C6 alkyl groups, the 2 R _4s may be the same as The carbon atoms to which these groups are bonded together form a ring, n represents 0, 1, 2 or 3); L ₃ represents -C(=O)- or -S(=O) ₂ -; R ₅ represents that it can also have A C2-C6 alkenyl group with a substituent or a C2-C6 alkynyl group that may also have a substituent]. [2] The compound of [1] or a salt thereof, wherein R ₁ is a hydrogen atom, a halogen atom or a C1-C6 alkyl group which may have a substituent. [3] The compound of [1] or [2] or a salt thereof, wherein R ₂ is a C1-C6 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, or a substituent. C3-C10 cycloalkyl. [4] The compound of any one of [1] to [3] or a salt thereof, wherein two of A1, A2 and A3 are the same or different, and are nitrogen atoms or sulfur atoms that may also have substituents, and The remainder are carbon atoms which may have substituents. [5] The compound or salt thereof according to any one of [1] to [4], wherein A1 is a carbon atom with a substituent or a nitrogen atom with a substituent, and the substituent is: selected from a hydrogen atom , the halogen atom may also have a C1-C6 alkyl group of Rb, a C2-C6 alkenyl group of Rb, a C3-C10 cycloalkyl group of Rc, or a C4-C10 cycloalkenyl group of Rc, It may also have at least one of the group consisting of a saturated heterocyclic group with 4 to 10 members of Rc and an unsaturated heterocyclic group with 5 to 10 members of Rc (Rb and Rc are the same as above). [6] The compound or salt thereof according to any one of [1] to [5], wherein the substituent of A3 is selected from the group consisting of hydrogen atom, halogen atom, cyano group, C1-C6 alkyl group and C1-C6 halogen At least one member of the group consisting of alkyl groups. [7] The compound or salt thereof according to any one of [1] to [6], wherein L ₂ is

[Chemical formula 4]

(In the formula,

[Chemical formula 5]

It is a saturated heterocyclic group with 1 or 2 nitrogen atoms as 4 to 6 members of the heteroatom, in which N represents a nitrogen atom, and R ₃ is a hydrogen atom or a methyl group, and R ₄ is a halogen atom, a cyano group, a hydroxyl group, or C1 -C3 alkyl, methoxy, C1-C3 haloalkyl, dimethylaminomethyl or ethoxymethyl, and when there are multiple R _4s , the multiple R _4s may be the same or different, n is 0, 1 or 2). [8] The compound or salt thereof according to any one of [1] to [7], wherein L ₃ is -C(=O)-. [9] The compound or salt thereof according to any one of [1] to [8], wherein R ₅ is vinyl or 1-propynyl. [10] The compound or salt thereof according to any one of [1] to [9], wherein R ₅ is a vinyl group. [11] The compound or salt thereof according to any one of [1] to [10], wherein X is CH. [12] The compound or salt thereof according to any one of [1] to [11], wherein L ₁ is -NH-CH ₂ -. [13] The compound or salt thereof according to any one of [2] to [12], wherein R ₁ is a chlorine atom. [14] The compound or salt thereof according to any one of [1] to [13], wherein R ₂ is a C1-C6 alkyl group. [15] The compound or salt thereof according to any one of [1] to [14], wherein R ₂ is tert-butyl. [16] The compound or salt thereof according to any one of [4] to [15], wherein A1 is a nitrogen atom that may also have a substituent, A2 is a nitrogen atom that may also have a substituent, and A3 is a nitrogen atom that may also have a substituent. The carbon atom of the substituent. [17] The compound or salt thereof according to any one of [7]~[16], wherein L ₂ is

[Chemical formula 6]

(In the formula,

[Chemical Formula 7]

It is a saturated heterocyclic group with 4 to 5 members containing 1 nitrogen atom as a heteroatom, where N represents a nitrogen atom, R ₃ represents a hydrogen atom, R ₄ is a halogen atom, C1-C2 alkyl group or methoxy group, R ₄ When there are a plurality of R 4's, the plurality of R ₄ 's may be the same or different, and n is 0, 1 or 2). [18] The compound or salt thereof according to any one of [1] to [17], wherein the compound is selected from the following compound group: ・N-(1-propenyl azedine-3-yl)-2 -(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide ; ・N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methane base)-1-isopropyl-4-methyl-1H-imidazole-5-carboxamide; ・N-(1-propenyl azedine-3-yl)-2-(((5-( tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-methyl-1H-imidazole-5-carboxamide; ・N-(1 -Acrylyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-( Difluoromethyl)-1-isopropyl-1H-imidazole-5-carboxamide; ・N-(1-propenyl azedine-3-yl)-2-(((5-(tert- Butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-isopropyl-1H-imidazole-5-carboxamide; ・N-((3S ,4S)-1-propenyl-4-fluoropyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )Methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide; ・N-((3S,4S)-1-acrylyl-4-fluoropyrrolidin-3-yl)- 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-fluoro-1-methyl-1H-imidazole-5-methyl Amide;・N-((3S,4S)-1-acrylyl-4-fluoropyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H- Indazol-3-yl)amino)methyl)-4-chloro-1-methyl-1H-imidazole-5-carboxamide; ・N-((3R,4R)-1-propenyl-4 -methylpyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1 -Methyl-1H-imidazole-5-carboxamide; ・N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro- 1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1-(1-isopropylpyrrolidin-3-yl)-1H-imidazole-5-carboxamide ; ・(S)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl) Amino)methyl)-4-chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-methamide;・N-(1-propenyl azedine-3-yl)-2 -(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(tetrahydro-2H-piran-4- base)-1H-imidazole-5-carboxamide;・(R)-N-(1-acrylyl azedine-3-yl)-2-(((5-(tert-butyl)-6 -Chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-carboxamide;・N-(1-propene Azobutin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1 -(1-methylpiperidin-4-yl)-1H-imidazole-5-methamide; ・N-(1-propenyl azedine-3-yl)-2-(((5-( tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(tetrahydro-2H-piran-3-yl)-1H-imidazole- 5-Formamide;・N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl) )Amino)methyl)-4-chloro-1-cyclopentyl-1H-imidazole-5-carboxamide; ・tert-butyl 3-(5-((1-acrylyl azetidine-3 -yl)aminoformyl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1H-imidazole -1-yl) azedine-1-carboxylate; ・N-(1-acrylyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro -1H-indazol-3-yl)amino)methyl)-4-chloro-1-(1-isopropylazetidin-3-yl)-1H-imidazole-5-methamide;・N -(1-Acrylyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)- 4-Chloro-1-(4-methoxycyclohexyl)-1H-imidazole-5-carboxamide; ・(R)-N-(1-propenyl azedine-3-yl)-2- (((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(1-(2,2-difluoroethyl )pyrrolidin-3-yl)-1H-imidazole-5-carboxamide; ・(R)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert -Butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(1-isopropylpyrrolidin-3-yl)-1H-imidazole-5 -Formamide; ・(S)-N-(1-acrylyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole- 3-yl)amino)methyl)-4-chloro-1-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-1H-imidazole-5-carboxamide; ・( R)-N-(1-propenyl azedine-3-yl)-1-(1-allylpyrrolidin-3-yl)-2-(((5-(tert-butyl)- 6-Chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1H-imidazole-5-carboxamide; ・(R)-N-(1-acrylyl azetidine -3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(1-( Pyridin-2-yl)pyrrolidin-3-yl)-1H-imidazole-5-carboxamide; and N-(1-propenyl azedine-3-yl)-2-(((5- (tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-((3R,5R)-1-(2,2-difluoroethyl) (yl)-5-methylpyrrolidin-3-yl)-1H-imidazole-5-carboxamide. [19] An inhibitor of the G12C mutation of RAS, which uses a compound or a salt thereof according to any one of [1] to [18] as an active ingredient. [20] A medicine containing the compound of any one of [1] to [18] or a salt thereof. [21] A pharmaceutical composition containing a compound according to any one of [1] to [18] or a salt thereof and a pharmaceutically acceptable carrier. [22] An anti-tumor agent containing the compound of any one of [1] to [18] or a salt thereof as an active ingredient. [23] An anti-tumor agent for oral administration, which contains the compound of any one of [1] to [18] or a salt thereof as an active ingredient. [24] The use of a compound or a salt thereof according to any one of [1] to [18] is used to manufacture an inhibitor of the G12C mutation of KRAS. [25] The use of a compound or salt thereof according to any one of [1] to [18], for the manufacture of pharmaceutical compositions. [26] The use of a compound or a salt thereof according to any one of [1] to [18], for producing an anti-tumor agent. [27] Use of a compound or a salt thereof according to any one of [1] to [18], for the manufacture of an anti-tumor agent for oral administration. [28] The use of a compound or salt thereof according to any one of [1] to [18] is used to prevent and/or treat tumors. [29] A commercial kit that simultaneously contains as an active ingredient a compound or a salt thereof according to any one of [1] to [18] and instructions for using the compound or a salt thereof in prevention or treatment Target tumor. [30] The compound of any one of [1] to [18] or its salt is used as an inhibitor of the G12C mutation of KRAS. [31] The compound or salt thereof according to any one of [1] to [18], which is used as medicine. [32] The compound or salt thereof according to any one of [1] to [18] is used for preventing and/or treating tumors. [33] The compound or salt thereof according to any one of [1] to [18], which is used for oral administration to prevent and/or treat tumors. [34] A method for inhibiting the G12C mutation of KRAS, comprising administering an effective amount of a compound or a salt thereof according to any one of [1] to [18] to a subject in need of the method. [35] A method for preventing and/or treating tumors, comprising administering an effective amount of a compound or a salt thereof according to any one of [1] to [18] to a subject in need of the method. [36] A method for preventing and/or treating tumors, comprising orally administering an effective amount of a compound or a salt thereof according to any one of [1] to [18] to a subject in need of the method. [37] An anti-tumor agent containing a compound or a salt thereof according to any one of [1] to [18] and one or more other anti-tumor agents as active ingredients. [38] An anti-tumor agent containing the compound of any one of [1] to [18] or a salt thereof as an active ingredient, characterized in that it is administered in combination with one or more other anti-tumor agents. [39] The use of a compound or salt thereof according to any one of [1] to [18] and one or more other anti-tumor agents, for the treatment of tumors. [40] The use of a compound or salt thereof as described in any one of [1] to [18] and one or more other anti-tumor agents, is used to manufacture anti-tumor agents. [41] A compound or a salt thereof according to any one of [1] to [18] for treating tumors, characterized in that it is administered in combination with one or more other anti-tumor agents. [42] A combination of a compound or salt thereof according to any one of [1] to [18] and one or more other anti-tumor agents is used to treat tumors. [43] A method for treating tumors, which includes administering to a subject in need of the method an effective amount of a compound or salt thereof according to any one of [1] to [18] and an effective amount of one or more other antibodies. Oncology Agents.

[Effects of the invention] The indazole compound represented by formula (I) or its salt can be used as an anti-cancer agent by causing functional inhibition of KRAS on G12C mutation-positive cancer cells of KRAS and exerting an anti-tumor effect.

[Form used to implement the invention] The compound represented by the above formula (I) of the present invention has an indazole and a heteroaryl group as its basic structure, and is a novel compound that has not been described in any of the aforementioned prior art documents.

In the description of the group in this specification, "CA-CB" represents a group having carbon numbers of A to B. For example, "C1-C6 alkyl" represents an alkyl group having 1 to 6 carbon atoms, and "C6-C14 aromatic hydrocarbon group" represents an oxy group to which an aromatic hydrocarbon group having 6 to 14 carbon atoms is bonded. Also, "members A~B" means that the number of atoms (number of ring members) constituting the ring is A~B. Specifically, the so-called "saturated heterocyclic group with 4 to 10 ring members" means a saturated heterocyclic group with 4 to 10 ring members.

In the description of symbols in this specification, C means a carbon atom, N means a nitrogen atom, S means a sulfur atom, O means an oxygen atom, and H means a hydrogen atom. In addition, a double line in a chemical formula means a double bond, and a dotted line in one of the double lines means a single bond or a double bond.

In this specification, unless expressly stated otherwise, "substituent" may include, for example, a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a pendant oxygen group, a carbonyl group, a carboxyl group, an amine methyl group, Alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, cycloalkyl, cycloalkenyl, cycloalkyl-alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxy- Alkyl, cycloalkoxy, cycloalkyl-alkoxy, cycloalkyl-haloalkyl, alkylthio, cycloalkyl-alkylthio, mono or dialkylamino, alkylamino Alkyl, cycloalkyl-alkylamino, aromatic hydrocarbon, aralkyl, aralkyloxy, acyl, alkylcarbonyl, arylcarbonyl, acyloxy, alkylcarbonyloxy, aryl Carbonyloxy group, alkoxycarbonyl group, aralkyloxycarbonyl group, saturated or unsaturated heterocyclic group, saturated heterocyclicoxy group, etc., when the aforementioned substituents are present and there is no express statement otherwise, their number Typically 1, 2 or 3, and preferably 1 or 2, with 1 being the best.

In this specification, the "halogen atom" specifically includes a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom, and is preferably a chlorine atom, a fluorine atom, or a bromine atom, with a chlorine atom or a fluorine atom being preferred.

In this specification, "alkyl" represents a linear or branched saturated hydrocarbon group, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl. base, tert-butyl, n-pentyl, isopentyl, hexyl, heptyl and other C1-C10 alkyl groups, and preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, C1-C6 alkyl groups such as isobutyl and tert-butyl, with methyl, ethyl and tert-butyl being more preferred.

In this specification, "haloalkyl" means the aforementioned alkyl group having at least 1 halogen atom (preferably 1 to 10, and preferably 1 to 3), and examples thereof include fluoromethyl, difluoromethyl, Trifluoromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,1,1-trifluoroethyl, 1-fluoro-n-propyl, 1,1,1 -C1-C6 haloalkyl groups such as trifluoro-n-propyl, perfluoro-n-propyl, and perfluoroisopropyl, and preferably trifluoromethyl, 1-fluoroethyl, and 1,1-difluoro Ethyl, 1,1,1-trifluoroethyl.

In this specification, "hydroxyalkyl" means the above-mentioned alkyl group having at least 1 hydroxyl group (preferably 1 to 10, and preferably 1 to 2), and examples thereof include hydroxymethyl, hydroxyethyl, and 1-hydroxyl. Propyl, 2-hydroxybutyl and other C1-C6 hydroxyalkyl groups.

In this specification, "cyanoalkyl" refers to the aforementioned alkyl group having at least 1 cyano group (preferably 1 to 10, and preferably 1 to 2). Examples include cyanomethyl, cyanoethyl group, 1-cyanopropyl, 2-cyanobutyl and other C1-C6 cyanoalkyl groups.

In this specification, "cycloalkyl" means a monocyclic, cross-linked cyclic or polycyclic saturated hydrocarbon group, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclodecyl. The base is a C3-C10 cycloalkyl group, and is preferably cyclopropyl, cyclobutyl, or cyclopentyl, with cyclobutyl and cyclopentyl being particularly preferred.

In this specification, "cycloalkenyl" means a monocyclic, cross-linked cyclic or polycyclic unsaturated hydrocarbon group with at least 1 carbon-carbon double bond (for example, 1 to 2, and preferably 1). , examples include C4-C10 cycloalkenyl groups such as cyclobutenyl, cyclopentenyl, cyclopentenyl, cycloheptenyl, cyclodecenyl, etc., and preferably cyclobutenyl, cyclopentenyl, cyclodeenyl, etc. As the pentenyl group, cyclobutenyl and cyclopentenyl are particularly preferred.

In this specification, "cycloalkyl-alkyl" means the alkyl group having at least one cycloalkyl group, and examples thereof include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, C3-C10 cycloalkyl-C1-C4 alkyl groups such as cyclohexylisopropyl, cyclohexyl 1-methyl-4-isopropyl and cycloheptylmethyl, and preferably cyclohexylmethyl.

In this specification, the so-called "unsaturated hydrocarbon group" means a linear or branched unsaturated hydrocarbon group containing at least one carbon-carbon double or triple bond. Examples include vinyl, allyl, methylvinyl, 1 -C2-C10 unsaturated hydrocarbon groups such as propenyl, butenyl, pentenyl, hexenyl, ethynyl, 2-propynyl, etc., and preferably C2-C6 containing at least one carbon-carbon double or triple bond As linear or branched hydrocarbon groups, vinyl, allyl, and 1-propenyl are preferred, and vinyl is the most preferred.

In this specification, "alkenyl" means a linear or branched unsaturated hydrocarbon group with at least one double bond (for example, 1 to 2, and preferably 1), and examples thereof include vinyl and allyl. , 1-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-, 2- or 3-butenyl, 2-, 3- or 4-pentenyl, 2-methyl-2 -C2-C10 alkenyl groups such as butenyl, 3-methyl-2-butenyl, 5-hexenyl, etc., and preferably vinyl, allyl, 1-propenyl, 2-methyl-2- C2-C6 alkenyl groups such as propenyl, vinyl is the best.

In this specification, "alkynyl" means a linear or branched unsaturated hydrocarbon group with at least one triple bond (for example, 1 to 2, and preferably 1). Examples include ethynyl, 1- or 2-propynyl, 1-, 2- or 3-butynyl, 1-methyl-2-propynyl and other C2-C10 alkynyl groups, and preferably ethynyl, 2-propynyl and other C2-C6 Alkenyl, 2-propynyl is the best.

In this specification, "alkoxy" means an oxy group having the above-mentioned alkyl group, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and isobutoxy. , sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy and hexyloxy and other C1-C6 alkoxy groups, and preferably methoxy, ethoxy, with methoxy Better.

In this specification, "haloalkoxy" means the aforementioned alkoxy group having at least 1 (preferably 1 to 13, and preferably 1 to 3) halogen atoms. Examples include fluoromethoxy, difluoro Methoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy, 1,1-difluoroethoxy, 1,1,1-trifluoroethoxy, monofluoro-n-propoxy base, perfluoro-n-propoxy group, perfluoro-isopropoxy group and other C1-C6 haloalkoxy groups, and preferably fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group.

In this specification, "alkoxy-alkyl" means the alkyl group having at least one alkoxy group, and examples thereof include methoxymethyl, ethoxymethyl, methoxyethyl, and ethoxy. Ethyl, methoxypropyl, methoxy-n-yl, methoxypentyl, methoxyhexyl and methoxyheptyl, propoxyethyl, butoxyethyl and other C1-C4 alkyl Oxygen-C1-C10 alkyl, and preferably C1-C2 alkoxy-C1-C3 alkyl such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, etc. Methoxymethyl and methoxyethyl are preferred.

In this specification, "cycloalkoxy" means an oxygen group having the aforementioned cycloalkyl group, and examples thereof include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy. C3-C10 cycloalkoxy group, and preferably cyclobutyloxy group, cyclopentyloxy group or cyclohexyloxy group.

In this specification, "cycloalkyl-alkoxy" means the aforementioned alkoxy group having at least one aforementioned cycloalkyl group, and examples thereof include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, C3-C10 cycloalkyl-C1-C4 alkoxy groups such as cyclohexylmethoxy and cycloheptylmethoxy, and preferably cyclohexylmethoxy.

In this specification, "cycloalkyl-haloalkyl" means the aforementioned haloalkyl group having at least one aforementioned cycloalkyl group, and examples thereof include cyclopropylfluoromethyl, cyclobutylfluoromethyl, and cyclopentylfluoromethyl. C3-C10 cycloalkyl-C1-C4 haloalkyl groups such as cyclohexylfluoromethyl and cycloheptylfluoromethyl, and preferably cyclohexylfluoromethyl.

In this specification, "alkylthio group" means a thioxy group having the above-mentioned alkyl group, and examples thereof include methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n- Butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, hexylthio and other C1-C6 alkylthio groups, and preferably methylthio , Ethylthio.

In this specification, "cycloalkyl-alkylthio" means the aforementioned alkylthio group having at least one aforementioned cycloalkyl group, and examples thereof include cyclopropylmethylthio, cyclobutylmethylthio, and cyclopentyl. C3-C7 cycloalkyl-C1-C4 alkylthio groups such as methylthio group, cyclohexylmethylthio group and cycloheptylmethylthio group, and preferably cyclohexylmethylthio group.

In this specification, the so-called "alkylamino group" means an amino group having one or two alkyl groups as described above. Specific examples include methylamino group, ethylamino group, dimethylamino group, and diethylamine group. C1-C6 alkylamino groups such as ethylmethylamino group and ethylmethylamino group, and preferably methylamino group, dimethylamino group and methylethylamino group.

In this specification, "monoalkylamino group" means an amino group having one alkyl group as described above, and examples thereof include methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n- Butylamino, isobutylamino, tert-butylamino, n-pentylamino, isopentylamino, hexylamino and other C1-C6 monoalkylamino groups, and preferably methylamine base.

In this specification, "dialkylamino group" means an amino group having two alkyl groups as described above, and examples thereof include dimethylamino group, diethylamino group, di(n-propyl)amino group, and diisopropyl group. Amino group, di(n-butyl)amine group, diisobutylamino group, di(tert-butyl)amine group, di(n-pentyl)amine group, diisopentylamine group, dihexyl group C2-C12 dialkylamino groups such as amine group, methylethylamino group, methylisopropylamino group, etc., and preferably dimethylamino group.

In this specification, "alkylaminoalkyl" means the alkyl group having at least one alkylamino group, and examples thereof include methylaminomethyl, methylaminoethyl, and ethylaminomethyl. , ethylaminopropyl and other C1-C6 alkylamino-C1-C6 alkyl groups, and preferably dimethylaminomethyl, dimethylaminoethyl.

In this specification, "cycloalkyl-alkylamino" means the above-mentioned alkylamino group having the above-mentioned cycloalkyl group, and the alkyl part of the alkylamino group is substituted with a cycloalkyl group. Examples thereof include cycloalkyl-alkylamino group. Propylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and cycloheptylmethylamino, etc. C3-C7 cycloalkyl-C1-C4 alkylamino , and is preferably a cyclobutylmethylamino group or a cyclohexylmethylamino group.

In this specification, "aromatic hydrocarbon group" means a cyclic substituent composed of carbon and hydrogen with an unsaturated bond, and contains 4e+2 (e is an integer above 1) electrons in the cyclic π electron system. Examples of the monocyclic or polycyclic aromatic hydrocarbon group include phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, and the like, and phenyl is preferred.

In this specification, "aralkyl" means the alkyl group substituted by the aromatic hydrocarbon group, and examples thereof include C7- benzyl, phenylethyl, phenylpropyl, naphthylmethyl, naphthylethyl, etc. C16 aralkyl group, preferably benzyl.

In this specification, "aralkyloxy" means an oxygen group having the above-mentioned aralkyl group, and examples thereof include C7 groups such as benzyloxy, phenethyloxy, naphthylmethyloxy, and benzylmethyloxy. -C20 aralkyloxy group, preferably benzyloxy group.

In this specification, "carboxylic acid group" represents a carbonyl group having the aforementioned alkyl group or aryl group, and represents a carbonyl group having a C1-C16 substituent such as methylcarbonyl, ethylcarbonyl, phenylcarbonyl, etc., preferably methylcarbonyl, ethylcarbonyl, etc. base carbonyl.

In this specification, "alkylcarbonyl" means a carbonyl group having the above-mentioned alkyl group, and is also included in the alias "carboxyl group". Examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, C1-C6 alkylcarbonyl groups such as hexylcarbonyl group, and preferably methylcarbonyl group. In addition, in the present invention, C1-C6 alkylcarbonyl group means (C1-C6 alkyl)carbonyl group.

In this specification, "arylcarbonyl" means a carbonyl group having the above-mentioned aromatic hydrocarbon group, and is also included in the alias "acyl group". Examples include phenylcarbonyl, naphthylcarbonyl, benzylcarbonyl, anthracenylcarbonyl, biphenylcarbonyl, tetrahydronaphthylcarbonyl, (C6-C20 aryl) carbonyl groups such as 2,3-dihydro-1,4-dioxanylcarbonyl group, dihydroindenylcarbonyl group and phenanthrenylcarbonyl group.

In this specification, "acyloxy" means an oxygen group having the aforementioned C1-C16 acyl group, preferably an acetyloxy group, an ethyl acyloxy group, a phenyl acyloxy group, etc. and a group having a C1-C16 substituent. The oxygen group bonded by the acyl group is preferably an acetyloxy group, tert-butylcarbonyloxy group, or phenylcarbonyloxy group.

In this specification, "alkylcarbonyloxy" means an oxygen group having the above-mentioned alkylcarbonyl group, and is also included in the alias "carboxyloxy". Examples include methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyl Oxy group, n-pentylcarbonyloxy group, isopentylcarbonyloxy group, hexylcarbonyloxy group and other (C1-C6 alkyl)carbonyloxy groups, and preferably acetyloxy group, tert-butylcarbonyloxy group.

In this specification, "arylcarbonyloxy" means an oxygen group having the above-mentioned arylcarbonyl group, and also includes the alias "acyloxy group". Examples include phenylcarbonyloxy, naphthylcarbonyloxy, benzylcarbonyloxy, anthracenylcarbonyloxy, biphenylcarbonyloxy, tetrahydronaphthylcarbonyloxy, Carbonyloxy group, 2,3-dihydro-1,4-dioxanaphthylcarbonyloxy group, indenylcarbonyloxy group and phenanthrenylcarbonyloxy group (C6-C14 aryl)carbonyloxy group, And it is preferably phenylcarbonyloxy.

In this specification, "alkoxycarbonyl" means a carbonyl group having the above-mentioned alkoxy group, and examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutyl Oxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl and hexyloxycarbonyl (C1-C6 alkoxy) carbonyl groups, and preferably methoxycarbonyl, ethoxy Carbonyl group, tert-butoxycarbonyl group, tert-butoxycarbonyl group is preferred.

In this specification, "aralkyloxycarbonyl" means a carbonyl group having the above-mentioned aralkyloxy group, and examples thereof include benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethyloxycarbonyl, and benzylmethyl. It is an oxycarbonyl group such as (C6-C20 aralkyl)oxycarbonyl group, and preferably benzyloxycarbonyl group.

In this specification, "saturated heterocyclic group" means a monocyclic ring having at least 1 (preferably 1 to 5, and preferably 1 to 3) hetero atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. Or a polycyclic saturated heterocyclic group, such as aziridinyl, azetidinyl, imidazolidinyl, morpholinyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperidinyl base, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, thiazolidinyl, thiacyclohexanyl, oxazolidinyl, phenylinyl group, etc., and preferably azebutidinyl, pyrrolidinyl, piperidinyl, with azebutidinyl and pyrrolidinyl being preferred.

In this specification, "unsaturated heterocyclic group" means a monocyclic ring having at least 1 (preferably 1 to 5, and preferably 1 to 3) hetero atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. Formula or polycyclic completely unsaturated or partially unsaturated heterocyclic groups, such as imidazolyl, thienyl, pyrrolyl, oxazolyl, iso Azolyl, thiazolyl, isothiazolyl, thiadiazolyl, Diazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazyl (pyrazyl), pyrimidinyl, pyridyl base, indolyl, isoindolyl, indazolyl, triazolopyridyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, furyl, benzofuranyl, Purinyl, quinolyl, isoquinolinyl, quinazolinyl, quinoxalyl, methylenedioxyphenyl, ethyldioxyphenyl, dihydrobenzofuranyl, etc. , and should be imidazolyl, pyrazolyl, thiazolyl, iso Azole group, oxazolyl group, furyl group, imidazolyl group, pyrazolyl group, thiazolyl group are preferred, and imidazolyl group is the most preferred.

In this specification, "saturated heterocyclic oxy" means an oxy group having the aforementioned saturated heterocyclic group, and examples thereof include morpholinyloxy, 1-pyrrolidinyloxy, piperidinooxy, and piperidinyloxy. baseoxy, 4-methyl-1-piper baseoxy, tetrahydrofuryloxy, tetrahydropyranyloxy, tetrahydrothiophenyloxy, thiazolidinyloxy, azolidinyloxy, etc., and preferably azetidinyloxy, pyrrolidinyloxy.

In the compound represented by the general formula (I) of the present invention, X represents a nitrogen atom or CH, and is preferably CH.

In the compound represented by the general formula (I) of the present invention, _R1 is a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a carboxyl group, or a C1-C6 alkyl group with a substituent, or C2-C6 alkenyl group with substituent, C2-C6 alkynyl group which may also have substituent, C3-C10 cycloalkyl group which may also have substituent, aromatic hydrocarbon group of C6-C10, saturated heterogeneous group with 4 to 10 members Ring group or unsaturated heterocyclic group with 5 to 10 members.

The "halogen atom" represented by R ₁ is preferably a fluorine atom, a chlorine atom, or a bromine atom, with a chlorine atom being particularly preferred.

The "C1-C6 alkyl group" in the "C1-C6 alkyl group which may have a substituent" represented by _R1 is preferably methyl, ethyl, n-propyl, isopropyl (C1-C3 alkyl ), and methyl and ethyl are preferred, and methyl is more preferred.

The "substituent" in the "C1-C6 alkyl group which may have a substituent" represented by R ₁ can be exemplified by the aforementioned substituents, but is preferably a halogen atom, a cyano group, a hydroxyl group, and a fluorine atom, a chlorine atom, or a hydroxyl group. Atoms, cyano groups and hydroxyl groups are preferred.

The "C1-C6 alkyl group that may have a substituent" represented by R ₁ is preferably a C1-C6 alkyl group, and methyl, ethyl, and tert-butyl are preferred, and methyl and ethyl are more preferred. , Methyl group is particularly good.

The "C2-C6 alkenyl group" in the "C2-C6 alkenyl group which may have a substituent" represented by R ₁ is preferably vinyl, 1-propenyl, allyl or isopropenyl, and 1- Acrylic is preferred.

The "substituent" in the "C2-C6 alkenyl group which may have a substituent" represented by R ₁ can be exemplified by the aforementioned substituents, but is preferably a halogen atom or a hydroxyl group, and preferably a chlorine atom or a fluorine atom. .

The "C2-C6 alkenyl group which may have a substituent" represented by R ₁ is preferably 1-propenyl or 2-methyl-2-propenyl.

The "C2-C6 alkynyl group" in the "C2-C6 alkynyl group which may have a substituent" represented by _R1 is preferably an ethynyl group or a 1-propynyl group.

The "substituent" in the "C2-C6 alkynyl group which may have a substituent" represented by R ₁ can be exemplified by the aforementioned substituents, preferably a halogen atom or a hydroxyl group, and preferably a fluorine atom or a chlorine atom. .

The "C2-C6 alkynyl group which may have a substituent" represented by R ₁ is preferably a C2-C6 alkynyl group, and is preferably an ethynyl group or a 1-propynyl group.

The "C3-C10 cycloalkyl group" in the "C3-C10 cycloalkyl group which may have a substituent" represented by _R1 is preferably a cyclobutyl, cyclopentyl or cyclohexyl group.

The "substituent" in the "C3-C10 cycloalkyl group which may have a substituent" represented by _R1 can be exemplified by the aforementioned substituents, but is preferably a halogen atom, a C1-C6 alkyl group, and a methyl group. , ethyl group, n-propyl group, fluorine atom and chlorine atom are preferred.

The "C3-C10 cycloalkyl group which may have a substituent" represented by R ₁ is preferably a C3-C10 cycloalkyl group, and is preferably a cyclobutyl, cyclopentyl or cyclohexyl group.

The "C6-C10 aromatic hydrocarbon group" represented by R ₁ is preferably a phenyl group.

The "4 to 10-membered saturated heterocyclic group" represented by R ₁ is preferably a monocyclic or bicyclic 4 to 10-membered group having 1 to 5 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. A saturated heterocyclic group, and preferably a monocyclic 4-7 membered saturated heterocyclic group with 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, more preferably an aziridinyl group , pyrrolidinyl, piperidinyl.

The "unsaturated heterocyclic group of 5 to 10 members" represented by R ₁ is preferably a monocyclic or bicyclic 5 to 10 heteroatom with 1 to 5 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. A membered unsaturated heterocyclic group, and preferably a monocyclic 5-7 membered unsaturated heterocyclic group with 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, more preferably pyridine base.

R ₁ is preferably a hydrogen atom, a halogen atom, or a C1-C6 alkyl group which may have a substituent.

R ₁ is more preferably a hydrogen atom, a halogen atom, or a C1-C6 alkyl group.

R ₁ is more preferably a halogen atom or a C1-C6 alkyl group.

R ₁ is more preferably a halogen atom or a methyl group.

R ₁ is more preferably a chlorine atom or a methyl group.

R ₁ is preferably a chlorine atom.

In the compound represented by the general formula (I) of the present invention, R ₂ represents a hydrogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a carboxyl group, a C1-C6 alkyl group that may have a substituent, or a substituted C1-C6 alkyl group. The C2-C6 alkenyl group, the C2-C6 alkynyl group which may also have a substituent, the C3-C10 cycloalkyl group which may also have a substituent, the aromatic hydrocarbon group of C6-C10, the saturated heterocyclic group with 4 to 10 members Or an unsaturated heterocyclic group with 5 to 10 members.

The "C1-C6 alkyl group" in the "C1-C6 alkyl group which may have a substituent" represented by R ₂ is preferably methyl, ethyl, n-propyl, isopropyl, or n-butyl , tert-butyl, sec-butyl, isobutyl, n-pentyl, and methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl are preferred, Methyl, ethyl, and tert-butyl are more preferred, and tert-butyl is the most preferred.

The "substituent" in the "C1-C6 alkyl group which may have a substituent" represented by R ₂ can be exemplified by the aforementioned substituents, and is preferably a halogen atom, a cyano group, a hydroxyl group, or a C3-C7 cycloalkyl group. , and fluorine atom, chlorine atom, cyclopropyl group and cyclobutyl group are preferred.

The "C1-C6 alkyl group which may have a substituent" represented by R ₂ is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl , isobutyl, n-pentyl and other C1-C6 alkyl groups, and methyl, ethyl, isopropyl and tert-butyl are preferred, isopropyl and tert-butyl are preferred, and tert- Butyl is better.

The "C2-C6 alkenyl group" in the "C2-C6 alkenyl group which may have a substituent" represented by R ₂ is preferably vinyl, 1-propenyl, allyl, isopropenyl, and vinyl , isopropenyl is preferred.

The "substituent" in the "C2-C6 alkenyl group which may have a substituent" represented by R ₂ can be exemplified by the aforementioned substituents, but is preferably a halogen atom, a cyano group, a hydroxyl group, and a chlorine atom, a fluorine atom, or a hydroxyl group. Atoms are preferred, and fluorine atoms are more preferred.

The "C2-C6 alkenyl group which may have a substituent" represented by R ₂ is preferably a C2-C6 alkenyl group which may also have a halogen atom, and is represented by vinyl, 1-propenyl, 2-methyl-2- Preferred are propenyl and 1-(trifluoromethyl)vinyl, and vinyl and 1-(trifluoromethyl)vinyl are preferred.

The "C2-C6 alkynyl group" in the "C2-C6 alkynyl group which may have a substituent" represented by _R2 is preferably an ethynyl group or a 1-propynyl group.

The "substituent" in the "C2-C6 alkynyl group which may have a substituent" represented by R ₂ can be exemplified by the aforementioned substituents, preferably a halogen atom or a hydroxyl group, and preferably a fluorine atom or a chlorine atom. , fluorine atoms are better.

The "C2-C6 alkynyl group which may have a substituent" represented by R ₂ is preferably an ethynyl group or a 1-propynyl group.

The "C3-C10 cycloalkyl group" in the "C3-C10 cycloalkyl group which may have a substituent" represented by R ₂ is preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and is Propyl is preferred.

The "substituent" in the "C3-C10 cycloalkyl group which may have a substituent" represented by R ₂ can be exemplified by the aforementioned substituents, preferably a halogen atom, a C1-C6 alkyl group, or a C1-C6 halogen Alkyl group, preferably fluorine atom, chlorine atom, methyl, ethyl, n-propyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluorine atom, methyl, ethyl, trifluoromethyl Methyl is better.

The "C3-C10 cycloalkyl group which may have a substituent" represented by R ₂ is preferably a C3-C10 cycloalkyl group which may also have a C1-C6 haloalkyl group, and is represented by a cyclopropyl group, a cyclobutyl group, a cycloalkyl group, or a cycloalkyl group. Pentyl, cyclohexyl and 1-(trifluoromethyl)cyclopropyl are preferred.

The "C6-C10 aromatic hydrocarbon group" represented by R ₂ is preferably a phenyl group.

The "4 to 10-membered saturated heterocyclic group" represented by R ₂ is preferably a monocyclic or bicyclic 4 to 10-membered group having 1 to 5 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. A saturated heterocyclic group, and preferably a monocyclic 4-7 membered saturated heterocyclic group with 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, more preferably an aziridinyl group , pyrrolidinyl, piperidinyl, tetrahydropyranyl.

The "unsaturated heterocyclic group with 5 to 10 members" represented by R ₂ is preferably a monocyclic or bicyclic 5 to 10 heteroatom with 1 to 5 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. A membered unsaturated heterocyclic group, and preferably a monocyclic 5-7 membered unsaturated heterocyclic group with 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, preferably pyridine base.

R ₂ is preferably a C1-C6 alkyl group which may have a substituent, a C2-C6 alkenyl group which may have a substituent, or a C3-C10 cycloalkyl group which may have a substituent.

R ₂ is preferably a C1-C6 alkyl group, a C2-C6 alkenyl group which may also have a halogen atom, or a C3-C10 cycloalkyl group which may also have a C1-C6 haloalkyl group.

R ₂ is preferably C1-C6 alkyl, vinyl, 1-(trifluoromethyl)vinyl, or 1-(trifluoromethyl)cyclopropyl.

R ₂ is preferably C1-C6 alkyl.

R ₂ is preferably C3-C6 alkyl.

_R2 is preferably tert-butyl.

In the compound represented by the general formula (I) of the present invention, Ra is the same or different, and represents a hydrogen atom, a deuterium atom, or a C1-C6 alkyl group.

The "C1-C6 alkyl group" represented by Ra is preferably methyl or ethyl, and methyl is the most preferred.

Ra is preferably a hydrogen atom, a deuterium atom, or a methyl group, and is most preferably a hydrogen atom. In the compound represented by the general formula (I) of the present invention, L ₁ represents -NH-C(Ra) ₂ -. L ₁ is preferably -NH-C(Ra) ₂ , and one of the two Ra's is a hydrogen atom, and the other is a hydrogen atom, a deuterium atom, or a methyl group, and the most preferable one is -NH-CH ₂ -.

In the compound represented by the general formula (I) of the present invention, ring A represents a 5-membered unsaturated heterocyclic group which may have a substituent. Typically, Ring A represents a 5-membered unsaturated heterocyclic group which may have a substituent and has two double bonds in the ring. In ring A, A1, A2 and A3 are the same or different and represent a carbon atom which may have a substituent, a nitrogen atom, a sulfur atom or an oxygen atom which may have a substituent. Then, in ring A, one of A1, A2, and A3 is a nitrogen atom or a sulfur atom that may have a substituent, and two of the remaining A1, A2, and A3 are the same or different, indicating that they may also have substitution. The carbon atom of the group may also have a substituent of a nitrogen atom, a sulfur atom or an oxygen atom.

Ring A is preferably a group that may have a substituent and has two hydrogen atoms removed from imidazole, pyrazole, thiazole, or oxazole, and more preferably has a substituent, and has two hydrogen atoms removed from imidazole, pyrazole, or thiazole. The group formed by a hydrogen atom is preferably a group formed by removing two hydrogen atoms from imidazole, which may have a substituent.

The "5-membered unsaturated heterocyclic group" represented by ring A is preferably a group obtained by removing two hydrogen atoms from imidazole, pyrazole, thiazole, or oxazole, and preferably also has a substituent and is obtained from imidazole. A group formed by removing two hydrogen atoms from , pyrazole or thiazole, preferably a group formed by removing two hydrogen atoms from imidazole.

The "substituent" in the "5-membered unsaturated heterocyclic group which may have a substituent" represented by ring A can be exemplified by the substituents mentioned above, and is preferably a hydrogen atom, a halogen atom, a cyano group, or a nitro group. , amino group, hydroxyl group, carboxyl group, C1-C6 alkyl group which may also have a substituent, C2-C6 alkenyl group which may also have a substituent, C2-C6 alkynyl group which may also have a substituent, and a C2-C6 alkynyl group which may also have a substituent C3-C10 cycloalkyl group, C4-C10 cycloalkenyl group which may also have a substituent, C6-C10 aromatic hydrocarbon group which may also have a substituent, or a 4 to 10-membered saturated heterocyclic group which may have a substituent, It may also have an unsaturated heterocyclic group with 5 to 10 substituents.

The "halogen atom" contained in the substituent of ring A is preferably a fluorine atom or a chlorine atom.

The "C1-C6 alkyl group" in the "C1-C6 alkyl group that may also have a substituent" contained in the substituent of ring A is preferably methyl, ethyl, n-propyl, isopropyl, n- Butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, and methyl and ethyl are preferred.

The "substituent" in the "C1-C6 alkyl group which may have a substituent" contained in the substituent of ring A can be exemplified by the aforementioned substituents, but is preferably a halogen atom or a C1-C6 alkyl group which may have a substituent. C6 alkoxy group, C1-C6 alkylamino group which may also have a substituent, C3-C10 cycloalkyl group which may also have a substituent, C6-C10 aromatic hydrocarbon group which may also have a substituent, which may also have a substituent The base is a saturated heterocyclic group with 4 to 10 members, preferably a halogen atom, a C1-C6 alkoxy group, a C1-C6 alkylamine group, or a C3-C10 cycloalkyl group with a C1-C6 alkoxy group, The C6-C10 aromatic hydrocarbon group may also have a C1-C6 alkyl group and a saturated heterocyclic group with 4 to 10 members, preferably a halogen atom, a C1-C6 alkoxy group, a C1-C6 alkylamine group, a C3- C7 cycloalkyl, phenyl, phenyl substituted with 1 to 3 C1-C6 alkoxy groups, 4 to 10 membered saturated heterocyclic groups substituted with 1 to 3 C1-C6 alkyl groups, preferably fluorine atoms , methoxy, dimethylamino, cyclopentyl, phenyl, 3,5-dimethoxyphenyl, N-isopropyl-2-pyrrolidinyl.

The "C1-C6 alkyl group which may have a substituent" contained in the substituent of ring A is preferably a C1-C6 alkyl group which may have a substituent selected from the group consisting of: a halogen atom; A C1-C6 alkoxy group which may have a substituent, a C1-C6 alkylamine group which may have a substituent, a C3-C10 cycloalkyl group which may have a substituent, or a C6-C10 aromatic group which may have a substituent Family hydrocarbon group, and a 4 to 10-membered saturated heterocyclic group that may have a substituent; preferably a C1-C6 alkyl group that may also have a substituent selected from the group consisting of: a halogen atom, C1- C6 alkoxy group, C1-C6 alkylamino group, C3-C10 cycloalkyl group which may also have C1-C6 alkoxy group, C6-C10 aromatic hydrocarbon group, and 4~ which may also have C1-C6 alkyl group A 10-membered saturated heterocyclic group; preferably a C1-C6 alkyl group that may also have a substituent selected from the group consisting of: fluorine atom, methoxy group, dimethylamino group, cyclopentyl group, Phenyl, 3,5-dimethoxyphenyl and N-isopropyl-2-pyrrolidinylmethyl; preferably methyl, ethyl, n-propyl, isopropyl and n-butyl , sec-butyl, tert-butyl, isobutyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-methoxy Ethyl, 2-(dimethylamino)ethyl, cyclopentylmethyl, benzyl, 3,5-dimethoxyphenylmethyl, N-isopropyl-2-pyrrolidinylmethyl base.

The "C2-C6 alkenyl group" in the "C2-C6 alkenyl group which may have a substituent" contained in the substituent of ring A is preferably vinyl or allyl.

The "substituent" in the "C2-C6 alkenyl group which may have a substituent" contained in the substituent of ring A can be exemplified by the above-mentioned substituents, and is preferably a halogen atom, and a fluorine atom or a chlorine atom. Better.

The "C2-C6 alkenyl group which may have a substituent" contained in the substituent of ring A is preferably vinyl or allyl.

The "C2-C6 alkynyl group" contained in the "C2-C6 alkynyl group which may have a substituent" contained in the substituent of ring A is preferably an ethynyl group or a 1-propynyl group.

The "substituent" in the "C2-C6 alkynyl group which may have a substituent" contained in the substituent of ring A can be exemplified by the aforementioned substituents, but is preferably a halogen atom, and a fluorine atom or a chlorine atom. good.

The "C2-C6 alkynyl group which may have a substituent" contained in the substituent of ring A is preferably an ethynyl group or a 1-propynyl group.

The "C3-C10 cycloalkyl group" included in the "C3-C10 cycloalkyl group which may have a substituent" contained in the substituent of ring A includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cycloalkyl, Hexyl, cycloheptyl, cyclodecyl, etc., and preferably C3-C7 cycloalkyl, preferably cyclopropyl, cyclopentyl, and cyclohexyl.

The "substituent" in the "C3-C10 cycloalkyl group which may have a substituent" contained in the substituent of ring A can be exemplified by the substituents mentioned above, and is preferably a hydroxyl group or a C1-C10 cycloalkyl group which may have a substituent. C6 alkyl, or C1-C6 alkoxy which may have a substituent, and hydroxyl, C1-C6 alkyl, C1-C6 alkoxy is preferred, hydroxyl, methyl, isopropyl and methoxy are preferred. good.

The "C3-C10 cycloalkyl group that may have a substituent" contained in the substituent of ring A is preferably a C3-C10 cycloalkyl group that may have a substituent selected from the group consisting of: hydroxyl, C1-C6 alkyl group which may also have a substituent and C1-C6 alkoxy group which may also have a substituent; Preferably it is a C3-C10 cycloalkyl group which may also have a substituent selected from the group consisting of : hydroxyl, C1-C6 alkyl and C1-C6 alkoxy; preferably C3-C7 cycloalkyl which may also have a substituent selected from the group consisting of: hydroxyl, C1-C6 alkyl and C1-C6 alkoxy; preferably cyclopropyl, cyclopentyl, cyclohexyl, 3,4-dihydroxycyclopentyl, 2-isopropyl-5-methyl-cyclohexyl, 4-methoxy cyclohexyl.

Examples of the "C4-C10 cycloalkenyl group" in the "C4-C10 cycloalkenyl group that may have a substituent" contained in the substituent of ring A include cyclobutenyl, cyclopentenyl, and cyclohexenyl , cycloheptenyl, cyclodecenyl, etc., and preferably C4-C7 cycloalkenyl, preferably cyclopentenyl.

The "substituent" in the "C4-C10 cycloalkenyl group which may have a substituent" contained in the substituent of ring A can be exemplified by the substituents mentioned above, and is preferably a halogen atom, and fluorine atom or chlorine atom. Better.

The "C4-C10 cycloalkenyl group which may also have a substituent" contained in the substituent of ring A is preferably a C4-C10 cycloalkenyl group, preferably a C4-C7 cycloalkenyl group, and preferably a cyclopentenyl group. .

The "C6-C10 aromatic hydrocarbon group" contained in the "C6-C10 aromatic hydrocarbon group that may have a substituent" contained in the substituent of ring A is preferably phenyl, naphthyl, or tetrahydronaphthyl, and is Phenyl is preferred.

The "substituent" in the "C6-C10 aromatic hydrocarbon group which may have a substituent" contained in the substituent of ring A can be exemplified by the above-mentioned substituents, but it is preferably a halogen atom, and fluorine atom, chlorine atom Atoms are better.

The "C6-C10 aromatic hydrocarbon group which may have a substituent" contained in the substituent of ring A is preferably a C6-C10 aromatic hydrocarbon group, and phenyl is preferred.

Among the "4 to 10-membered saturated heterocyclic group that may also have a substituent" contained in the substituent of ring A, the "4 to 10-membered saturated heterocyclic group" is preferably one having 1 to 5 nitrogen atoms. Monocyclic or bicyclic 4 to 10-membered saturated heterocyclic group of hetero atoms, oxygen atoms and sulfur atoms, preferably 1 to 3 hetero atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms The monocyclic 4-7 membered saturated heterocyclic group is preferably an azetidinyl, pyrrolidinyl or piperidinyl group.

The "substituent" in the "4 to 10-membered saturated heterocyclic group which may have a substituent" contained in the substituent of ring A can be exemplified by the substituents mentioned above, but is preferably C1 which may also have a substituent. -C6 alkyl, C1-C6 alkenyl, (C1-C6 alkyl) carbonyl, (C1-C6 alkoxy) carbonyl, C3-C10 cycloalkyl, C6-C10 aromatic hydrocarbon group, 4 to 10 members Saturated heterocyclic group, unsaturated heterocyclic group with 5 to 10 members, preferably C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkyl, C7-C16 aralkyl Base, C1-C6 alkenyl, (C1-C6 alkyl) carbonyl, (C1-C6 alkoxy) carbonyl, C3-C10 cycloalkyl, saturated heterocyclic group of 4 to 10 members, unsaturated heterocyclic group of 5 to 10 members Saturated heterocyclic group, preferably methyl, ethyl, isopropyl, 2,2-difluoroethyl, 2-methoxyethyl, benzyl, allyl, acetyl, tert-butyl Oxycarbonyl, cyclopropyl, oxycarbonyl, pyridyl, carboxylate, alkenyl, benzyl, preferably methyl, ethyl, isopropyl, methylcarbonyl, tert-butoxycarbonyl , 2,2-difluoroethyl, 2-methoxyethyl, benzyl, allyl.

The "4 to 10-membered saturated heterocyclic group that may also have a substituent" contained in the substituent of ring A is preferably N-tert-butoxycarbonyl azetidinyl, N-isopropyl azetidinyl, N-ethyl Azobutyridinyl, N-methylpyrrolidinyl, N-ethylpyrrolidinyl, N-acetylpyrrolidinyl, N-isopropylpyrrolidinyl, N-pyridinepyrrolidinyl, N-2- Methoxyethyl-pyrrolidinyl, N-cyclopropylpyrrolidinyl, N-oxetanylpyrrolidinyl, N-benzylpyrrolidinyl, N-carboxylate-azetidinyl, N- Difluoroethyl-pyrrolidinyl, N-prop-2-enyl-pyrrolidinyl, 1-(2,2-difluoroethyl)-2-methylpyrrolidin-3-yl, 1-(2 ,2-difluoroethyl)-5-methylpyrrolidin-3-yl, N-methylpiper methyl, N-difluoroethylpiper base, N-methylpiperidyl, N-difluoroethylpiperidyl, tetrahydropyranyl, tetrahydrofuranyl.

The "5-10-membered unsaturated heterocyclic group" contained in the substituent of ring A is preferably a pyridyl group.

The "substituent" in the "5 to 10-membered unsaturated heterocyclic group that may have a substituent" contained in the substituent of ring A can be exemplified by the aforementioned substituents, and is preferably a halogen atom, a hydroxyl group, or C1 -C6 alkyl group, preferably methyl group, ethyl group, hydroxyl group, fluorine atom and chlorine atom.

Among the "unsaturated heterocyclic groups of 5 to 10 members that may have substituents" contained in the substituents of ring A, the "unsaturated heterocyclic group of 5 to 10 members that may have substituents" is preferably 5 It is an unsaturated heterocyclic group with ~10 members, and pyridyl and N-methylpyridyl are preferred.

In formula (I), L ₂ represents

[Chemical formula 8]

here,

[Chemical formula 9]

It represents a saturated heterocyclic group with 4 to 8 members, which may also have 1 or 2 heteroatoms selected from sulfur atoms and oxygen atoms, and contains at least 1, preferably 1 or 2 nitrogen atoms.

R ₃ is a hydrogen atom or C1-C6 alkyl group.

R ₄ is a halogen atom, cyano group, nitro group, amine group, hydroxyl group, carboxyl group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group , C1-C6 alkylamino-C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C6 alkoxy-C1-C6 alkyl or C1-C6 hydroxyalkyl.

L ₂ ,

[Chemical formula 10]

It is preferably a 4- to 8-membered saturated heterocyclic group that does not contain sulfur atoms and oxygen atoms and contains at least one (preferably 1 or 2) nitrogen atoms, and is preferably an azetidinyl, pyrrolidinyl, or piperidinyl group.

L ₂ ,

[Chemical formula 11]

It is preferably a 4- to 8-membered saturated heterocyclic group that does not contain sulfur atoms and oxygen atoms and contains at least one (preferably 1 or 2) nitrogen atoms, and is preferably an azetidinyl, pyrrolidinyl, or piperidinyl group.

L ₂ ,

[Chemical formula 12]

It is preferably a 4 to 8-membered saturated heterocyclic group that does not contain sulfur atoms and oxygen atoms and contains at least 2 (preferably 2 or 3) nitrogen atoms, and is based on 1,3-diazetidinyl, imidazolidinyl, piperazolinyl, etc. The base is better.

The "C1-C6 alkyl group" represented by _R3 is preferably methyl or ethyl, and methyl is preferred. The "halogen atom" represented by R ₄ is preferably a fluorine atom. The "C1-C6 alkyl group" represented by R ₄ is preferably methyl or ethyl. The "C2-C6 alkenyl" represented by R ₄ is preferably vinyl or allyl. The "C2-C6 alkynyl group" represented by R ₄ is preferably an ethynyl group. The "C1-C6 alkoxy group" represented by R ₄ is preferably a methoxy group. The "C1-C6 haloalkyl group" represented by R ₄ is preferably fluoromethyl. The "C1-C6 cyanoalkyl group" represented by R ₄ is preferably cyanomethyl. The "C1-C6 alkylamino-C1-C6 alkyl group" represented by R ₄ is preferably N,N-dimethylaminomethyl. The "C1-C6 alkoxy-C1-C6 alkyl group" represented by R ₄ is preferably methoxymethyl or methoxyethyl, and methoxymethyl is more preferred. The "C1-C6 hydroxyalkyl group" represented by R ₄ is preferably hydroxymethyl or 2-hydroxyethyl, and hydroxymethyl is particularly preferred. When the same carbon atom is replaced by two R _4s , and the two R _4s are C1-C6 alkyl groups, the two R _4s can also form a ring together with the carbon atoms to which these groups are bonded. Examples of this ring include a structure obtained by removing two hydrogens bonded to the same carbon from a C3-C6 (preferably C3-C4, preferably C3) cycloalkane.

n is 0, 1, 2 or 3. It should be 0, 1 or 2, with 0 or 1 being better and 0 being the best.

In formula (I), preferably, the above-mentioned L ₂ represents a 4 to 6-membered saturated heterocyclic group containing one or two nitrogen atoms, R ₃ represents a hydrogen atom or a methyl group, and R ₄ represents a halogen atom, cyano group, or cyano group. Methyl, hydroxyl, C1-C2 alkyl, methoxy, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, dimethylaminomethyl, methoxymethyl or ethoxymethyl. In this embodiment, the same carbon atom is replaced by two R _4s , and when the two R _4s are C1-C2 alkyl groups, the two R _4s can also be combined with the carbon atoms bonded by these groups to form from C3-C5 (preferably C3) cycloalkane is a structure formed by removing two hydrogens bonded to the same carbon.

In the formula (I), it is preferably represented by L ₂

[Chemical formula 13]

here,

[Chemical formula 14]

Represents a 4 to 5-membered saturated heterocyclic group containing one N, R ₃ represents a hydrogen atom, n is 0, 1 or 2, R ₄ represents a halogen atom, methyl, ethyl or methoxy group.

In formula (I), L ₃ represents -C(=O)- or -S(=O) ₂ -, and is preferably -C(=O)-.

In formula (I), R ₅ represents a C2-C6 alkenyl group which may have a substituent or a C2-C6 alkynyl group which may have a substituent. The compound of the present invention or its salt has the structural characteristics shown in the aforementioned formula (I), and in particular, R ₅ has the above-mentioned structure, thereby specifically binding to the G12C mutated cysteine residue of KRAS.

The "C2-C6 alkenyl group" in the "C2-C6 alkenyl group which may have a substituent" represented by R ₅ is preferably vinyl, 1-propenyl, allyl, or isopropenyl.

The "substituent" in the "C2-C6 alkenyl group which may have a substituent" represented by R ₅ can be exemplified by the aforementioned substituents, and is preferably a halogen atom, a C1-C6 alkylamino group, or a C1-C6 Alkoxy group, 4 to 10-membered saturated heterocyclic group, preferably chlorine atom, methoxymethyl, dimethylamino group, piperidinyl group.

The "C2-C6 alkenyl group which may have a substituent" represented by R ₅ is preferably vinyl, 1-propenyl, 1-chlorovinyl, 2-chlorovinyl, 3-(dimethylamino) Prop-1-en-1-yl, 3-(piperidin-1-yl)prop-1-en-1-yl, 3-(methoxy)prop-1-en-1-yl.

The "C2-C6 alkynyl group" in the "C2-C6 alkynyl group which may have a substituent" represented by R ₅ is preferably an ethynyl group, a 1-propynyl group or a 2-propynyl group.

The "substituent" in the "C2-C6 alkynyl group which may have a substituent" represented by R ₅ can be exemplified by the substituents mentioned above, and is preferably a halogen atom, a C1-C6 alkyl group, or a C1-C6 alkoxy group. group, and fluorine atom, chlorine atom, methyl group and methoxy group are preferred.

The "C2-C6 alkynyl group which may have a substituent" represented by R ₅ is preferably an ethynyl group. R ₅ is preferably a C2-C6 alkenyl group which may have a substituent, preferably a C2-C3 alkenyl group which may have a substituent, and vinyl is the most preferred. In addition, R ₅ is preferably a C2-C6 alkenyl group which may have a substituent or a C2-C6 alkynyl group which may have a substituent (the substituent is selected from the group consisting of a halogen atom, a C1-C6 alkyl group and a C1-C6 alkyl group). A group consisting of an amino group, a C1-C6 alkoxy group, and a saturated heterocyclic group of 4 to 10 members), preferably a C2-C6 alkenyl group that may also have a substituent (the substituent is selected from the group consisting of halogen Atom, C1-C6 alkylamino group, C1-C6 alkoxy group, a group consisting of 4 to 10-membered saturated heterocyclic group) or a C2-C6 alkynyl group that may also have a substituent (the substituent is selected from halogen atom, C1-C6 alkyl group, C1-C6 alkoxy group), preferably a C2-C3 alkenyl group which may also have a substituent (the substituent is selected from the group consisting of chlorine atom, methoxymethyl, di (the group consisting of methylamino group and piperidinyl group), preferably C2-C3 alkenyl group, most preferably vinyl group.

In formula (I), when ring A is substituted with an alkyl group, the alkyl group should not be substituted by a C6-C10 aromatic hydrocarbon group, a 4-10-membered saturated heterocyclic group, or a 5-10-membered unsaturated heterocyclic group. .

When A1 is a carbon atom with a substituent or a nitrogen atom with a substituent, the substituent represents C1-C6 selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a carboxyl group, and may also have Rb The alkyl group may also have a C2-C6 alkenyl group with Rb, a C2-C6 alkynyl group with Rb, a C3-C10 cycloalkyl group with Rc, or a C3-C10 cycloalkenyl group with Rc, or At least one of the group consisting of an aromatic hydrocarbon group with Rc of C6-C10, a saturated heterocyclic group with 4 to 10 members of Rc, and an unsaturated heterocyclic group with 4 to 10 members of Rc. One kind. In this embodiment, Rb represents a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a carboxyl group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, and may have a substituent. A C6-C10 aromatic hydrocarbon group or a 4 to 10-membered saturated heterocyclic group that may also have a substituent, Rc represents halogen atom, cyano group, nitro group, amine group, hydroxyl group, carboxyl group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, C1-C6 alkylamino, C1-C6 alkylcarbonyl, C1-C6 alkoxy-C1-C6 alkyl, C7-C20 aralkyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, C6-C10 aromatic hydrocarbon group, 4-10 membered saturated heterocyclic group or 5-10 membered unsaturated heterocyclic group, When there are multiple Rbs, the multiple Rbs may be the same or different. When there are a plurality of Rcs, the plurality of Rcs may be the same or different.

Rb preferably represents a halogen atom, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C3-C10 cycloalkyl group, a C6-C10 aromatic hydrocarbon group that may have a substituent, or a 4~ that may have a substituent. 10-membered saturated heterocyclyl group, Rb preferably represents a halogen atom, a C1-C3 alkoxy group, a C1-C3 alkylamino group, a C3-C6 cycloalkyl group, a phenyl group that may have a substituent, or a 4 to 5-membered group that may have a substituent. Saturated heterocyclyl, More preferably, Rb is a chlorine atom, a fluorine atom, a methoxy group, a cyclopentyl group, a phenyl group, a 2,4-dimethoxyphenyl group, a dimethylamino group, or an N-isopropyl-pyrrolidinyl group. More preferably, Rb is a chlorine atom, a methyl group, an ethyl group, a cyano group, a difluoromethyl group, a trifluoromethyl group, or a 2,4-dimethoxyphenyl group.

Rc is preferably a halogen atom, hydroxyl group, C1-C6 alkyl group, C2-C6 alkenyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, C1-C6 alkylamino group, C1-C6 alkylcarbonyl group, C1 -C6 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxycarbonyl, C7-C20 aralkyl, saturated heterocyclic group with 4 to 10 members or any other group with 5 to 10 members Saturated heterocyclyl, Rc is preferably a halogen atom, hydroxyl group, C1-C3 alkyl group, C2-C3 alkenyl group, C1-C3 alkoxy group, C1-C3 haloalkyl group, C1-C3 alkylamino group, C1-C3 alkylcarbonyl group, C1-C3 alkoxy C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxycarbonyl, benzyl, 4-6 membered saturated heterocyclic group or 5-6 membered unsaturated heterocyclic group base, More preferably, Rc is a chlorine atom, a fluorine atom, a hydroxyl group, a methyl group, an ethyl group, an isopropyl group, an acetyl group, a methoxy group, a vinyl group, a difluoromethyl group, a trifluoromethyl group, or 2,2-difluoroethyl group. base, cyclopropyl, oxybenzyl, benzyl, tert-butoxycarbonyl, methoxyethyl, pyridyl.

A1 is preferably a carbon atom with a substituent or a nitrogen atom with a substituent. The substituent is preferably a hydrogen atom, a cyano group, a halogen atom, a C1-C6 alkyl group with Rb, or a C2-C6 group with Rb. Alkenyl group may also have a C3-C10 cycloalkyl group with Rc, may also have a C4-C10 cycloalkenyl group with Rc, may also have a saturated heterocyclic group with 4 to 10 members of Rc, may also have 4 to 10 members of Rc Member of the unsaturated heterocyclic group.

A1 is preferably a nitrogen atom with a substituent, and the substituent is a hydrogen atom, a halogen atom, or a C1-C6 alkyl group (it may also have a halogen atom, a C1-C6 alkoxy group, or a C1-C6 alkyl amine). group, C3-C10 cycloalkyl group, C6-C10 aromatic hydrocarbon group which may also have a substituent, a substituent group consisting of a 4 to 10-membered saturated heterocyclic group which may also have a substituent), C3-C10 ring Alkyl group (which may also have a substituent selected from the group consisting of hydroxyl, C1-C6 alkyl, C1-C6 alkoxy), C3-C10 cycloalkenyl, 4 to 10-membered saturated heterocyclic group ( It can also have a group selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkyl, C7-C16 aralkyl, C1-C6 alkenyl, C1-C6 alkyl Substituents of the group consisting of carbonyl group, C1-C6 alkoxycarbonyl group, C3-C10 cycloalkyl group, saturated heterocyclic group with 4 to 10 members, and unsaturated heterocyclic group with 5 to 10 members), 4 to 10 Member of the unsaturated heterocyclic group.

A1 is more preferably a nitrogen atom with a substituent, and the substituent is a hydrogen atom, a halogen atom, a C1-C6 alkyl group (selected from a halogen atom, a C1-C3 alkoxy group, a C1-C3 alkylamine group, a C3 -C6 cycloalkyl, a phenyl group that may have a substituent, a group consisting of a 4-5-membered saturated heterocyclic group that may have a substituent), C3-C6 cycloalkyl (which may also have a group selected from A substituent consisting of a hydroxyl group, a C1-C3 alkyl group, and a C1-C3 alkoxy group), a C3-C6 cycloalkenyl group, and a 4 to 5-membered saturated heterocyclic group (which may also have a group selected from the group consisting of C1- C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy-C1-C3 alkyl, benzyl, C1-C3 alkenyl, C1-C3 alkylcarbonyl, C1-C3 alkoxycarbonyl, C3 -C6 cycloalkyl, 4-6 membered saturated heterocyclic group, 5-6 membered unsaturated heterocyclic group (substituent of the group), 4-6 membered unsaturated heterocyclic group.

A1 is more preferably a nitrogen atom with a substituent, and the substituent is a hydrogen atom, a chlorine atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, Cyclopropyl, cyclopentyl, 3,4-dihydroxycyclopentyl, cyclohexyl, 2-isopropyl-5-methylcyclohexyl, 4-methoxycyclohexyl, cyclopentenyl, N-tert -Butoxycarbonyl ethylene-propyl, N-isopropyl ethylene-propyl, N-methylcarbonyl ethylene-propyl, N-methylpyrrolidinyl, N-ethylpyrrolidinyl, N-isopropyl pyrrolidinyl, N-(2,2-difluoroethyl)pyrrolidinyl, N-methylcarbonylpyrrolidinyl, N-methoxyethylpyrrolidinyl, N-benzylpyrrolidinyl, N - Oxypyrrolidinyl, N-methylpiperidinyl, N-(2,2-difluoroethyl)piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl.

A1 is more preferably a nitrogen atom with a substituent, and the substituent is a hydrogen atom, a chlorine atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, Cyclopentyl, 4-methoxycyclohexyl, N-isopropylaziridinyl, N-methylpyrrolidinyl, N-(2,2-difluoroethyl) )pyrrolidinyl, N-(2,2-difluoroethyl)piperidinyl, tetrahydrofuranyl, tetrahydropyranyl.

A2 is preferably a sulfur atom or a nitrogen atom with a substituent. The substituent is a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a carboxyl group, or a C1-C6 alkyl group with a substituent. A C2-C6 alkenyl group having a substituent and a C2-C6 alkynyl group which may also have a substituent.

A2 is preferably a nitrogen atom with a substituent, and the substituent is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, or a C1-C6 alkyl group.

A2 is preferably a nitrogen atom having a substituent, and the substituent is a hydrogen atom, a methyl group, or an ethyl group.

A2 is preferably a nitrogen atom having a hydrogen atom as a substituent.

A3 is preferably a carbon atom with a substituent or a nitrogen atom with a substituent. The substituent is a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a carboxyl group, or a C1-C6 alkane with a substituent. group, a C2-C6 alkenyl group which may also have a substituent, a C2-C6 alkynyl group which may also have a substituent, A3 is preferably a carbon atom with a substituent or a nitrogen atom with a substituent, and the substituent is a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a carboxyl group, a C1-C6 alkyl group, or a C1-C6 Haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, A3 is preferably a carbon atom with a substituent, and the substituent is a hydrogen atom, a halogen atom, a cyano group, a C1-C6 alkyl group, or a C1-C6 haloalkyl group, A3 is preferably a carbon atom with a substituent, and the substituent is a methyl group, an ethyl group, a difluoromethyl group, a chlorine atom, a fluorine atom, or a cyano group atom.

The combination of A1, A2 and A3 should be A1 is a substituted nitrogen atom, A2 is a nitrogen atom, A3 is a substituted carbon atom, or A1 is a nitrogen atom, A2 is a sulfur atom, A3 is a carbon atom with a substituent, or A1 is a carbon atom with a substituent, A2 is a nitrogen atom, A3 is a nitrogen atom with a substituent, or A1 is a sulfur atom, A2 is a nitrogen atom, and A3 is a carbon atom with a substituent.

The better combination of A1, A2 and A3 is A1 is a substituted nitrogen atom, A2 is a nitrogen atom, A3 is a substituted carbon atom, or A1 is a nitrogen atom, A2 is a sulfur atom, and A3 is a carbon atom having a substituent.

The best combination of A1, A2 and A3 is A1 is a nitrogen atom with a substituent, A2 is a nitrogen atom, and A3 is a carbon atom with a substituent.

The compound of the present invention is preferably the following compound or a salt _thereof . In formula (I), C1-C6 alkyl group which may have a substituent, C2-C6 alkenyl group which may also have a substituent, C2-C6 alkynyl group which may also have a substituent, C3-C10 cycloalkyl group which may also have a substituent, C6-C10 Aromatic hydrocarbon group, 4-10-membered saturated heterocyclic group or 5-10-membered unsaturated heterocyclic group; L ₁ represents -NH-C(Ra) ₂ -, Ra is the same or different, represents hydrogen atom, deuterium atom , C1-C6 alkyl; Ring A represents a 5-membered unsaturated heterocyclic group that may also have a substituent; one of A1, A2 and A3 is a nitrogen atom or a sulfur atom that may also have a substituent, and the remaining A1 , 2 of A2 and A3 are the same or different, indicating a carbon atom that may also have a substituent, a nitrogen atom, a sulfur atom or an oxygen atom that may have a substituent; the substituent of A1 is preferably a hydrogen atom or a cyano group , the halogen atom may also have a C1-C6 alkyl group of Rb, a C2-C6 alkenyl group of Rb, a C3-C10 cycloalkyl group of Rc, or a C4-C10 cycloalkenyl group of Rc, It may also have a saturated heterocyclic group with 4 to 10 members of Rc, or an unsaturated heterocyclic group with 4 to 10 members of Rc; Rb represents a halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, C1 -C6 alkoxy group, C1-C6 alkylamino group, C3-C6 cycloalkyl group, C6-C10 aromatic hydrocarbon group which may also have a substituent, or a 4 to 10-membered saturated heterocyclic group which may also have a substituent ; Rc represents halogen atom, cyano group, nitro group, amine group, hydroxyl group, carboxyl group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group , C1-C6 alkylamino, C1-C6 alkylcarbonyl, C1-C6 alkoxy-C1-C6 alkyl, C7-C20 aralkyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl , C6-C10 aromatic hydrocarbon group, 4 to 10-membered saturated heterocyclic group or 5 to 10-membered unsaturated heterocyclic group; when there are multiple Rbs, the multiple Rbs may be the same or different, and there are multiple Rcs In this case, the plurality of Rc may be the same or different. The substituent of A2 is a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a carboxyl group, or a C1-C6 alkyl group that may have a substituent. C2-C6 alkenyl group which may also have a substituent and C2-C6 alkynyl group which may also have a substituent; The substituent of A3 may be a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group or a carboxyl group. C1-C6 alkyl group with substituent, C2-C6 alkenyl group which may also have substituent, and C2-C6 alkynyl group which may also have substituent; L ₂ represents

[Chemical formula 15]

here

[Chemical formula 16]

Represents a 4 to 8-membered saturated heterocyclic group containing at least one nitrogen atom and 0 to 2 heteroatoms selected from sulfur atoms and oxygen atoms; R ₃ represents a hydrogen atom, C1-C6 alkyl group; R ₄ represents halogen Atom, cyano group, nitro group, amine group, hydroxyl group, carboxyl group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, C1-C6 Haloalkyl, C1-C6 alkylamino-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl or C1-C6 hydroxyalkyl; L ₃ represents -C(=O)-or- S(=O) ₂ -; R ₅ represents a C2-C6 alkenyl group which may have a substituent or a C2-C6 alkynyl group which may have a substituent.

Preferred are _the following compounds or their salts. In formula (I), , or a C3-C10 cycloalkyl group that may have a substituent; L ₁ represents -NH-C(Ra) ₂ -, and one of the two Ra is a hydrogen atom, and the other is a hydrogen atom, a deuterium atom, or a methyl group. group; Ra is the same or different, and is a hydrogen atom, a deuterium atom, or a methyl group; In terms of the combination of A1, A2, and A3 in ring A, A1 is a nitrogen atom with a substituent, A2 is a nitrogen atom, and A3 is a substituent. Carbon atom, or A1 is a nitrogen atom with a substituent, A2 is a sulfur atom, A3 is a carbon atom with a substituent, or A1 is a carbon atom with a substituent, A2 is a nitrogen atom, A3 is a nitrogen atom with a substituent, or A1 is a sulfur atom, A2 is a nitrogen atom, and A3 is a carbon atom with a substituent; the substituent of A1 is a hydrogen atom, a halogen atom, or a C1-C6 alkyl group (it may also have a halogen atom, C1-C6 A group consisting of an alkoxy group, a C1-C6 alkylamino group, a C3-C10 cycloalkyl group, a C6-C10 aromatic hydrocarbon group that may also have a substituent, and a 4 to 10-membered saturated heterocyclic group that may also have a substituent. group of substituents), C3-C10 cycloalkyl (which may also have a substituent selected from the group consisting of hydroxyl, C1-C6 alkyl, C1-C6 alkoxy), C3-C10 cycloalkenyl, 4 to 10-membered saturated heterocyclic group (can also have a group selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkyl, C7-C16 aralkyl, Composed of C1-C6 alkenyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C3-C10 cycloalkyl, 4-10-membered saturated heterocyclic group, 5-10-membered unsaturated heterocyclic group group of substituents), 4 to 10-membered unsaturated heterocyclic groups; the substituents of A2 are hydrogen atoms, halogen atoms, cyano groups, nitro groups, amino groups, hydroxyl groups, carboxyl groups, and C1- which may also have substituents. C6 alkyl group, C2-C6 alkenyl group which may also have a substituent, and C2-C6 alkynyl group which may also have a substituent; The substituents of A3 are hydrogen atoms, halogen atoms, cyano groups, nitro groups, amino groups, hydroxyl groups, Carboxyl group, C1-C6 alkyl group which may also have a substituent, C2-C6 alkenyl group which may also have a substituent, and C2-C6 alkynyl group which may also have a substituent; L ₂ represents 4~ containing one or two N 6-membered saturated heterocyclic group; R ₃ represents a hydrogen atom or a methyl group; n of R ₄ = 1 or 2, and represents a halogen atom, cyano group, hydroxyl, C1-C2 alkyl, methoxy group, C1-C2 haloalkane group, dimethylaminomethyl or ethoxymethyl; L ₃ represents -C (=O); R ₅ represents a C2-C6 alkenyl group which may also have a substituent or a C2-C6 group which may also have a substituent Alkynyl.

More preferably, the following compounds or salts thereof are: In formula (I), X represents CH; _R1 is a halogen atom, C1-C3 alkyl group, 1-propenyl group, or 2-methyl 2-propenyl group which may also have a substituent , or 1-methylcyclopropyl; L ₁ represents -NH-C(Ra) ₂ -, and one of the two Ra is a hydrogen atom, and the other is a hydrogen atom, a deuterium atom, or a methyl group, and Ra is the same Or different, it is a hydrogen atom, a deuterium atom, or a methyl group; in terms of the combination of A1, A2, and A3 in ring A, A1 is a nitrogen atom with a substituent, A2 is a nitrogen atom, and A3 is a carbon atom with a substituent, or A1 is a nitrogen atom with a substituent, A2 is a sulfur atom, and A3 is a carbon atom with a substituent; the substituent of A1 is a hydrogen atom, a halogen atom, or a C1-C6 alkyl group (selected from a halogen atom, C1-C3 Alkoxy group, C1-C3 alkylamino group, C3-C6 cycloalkyl group, a phenyl group that may also have a substituent, a group consisting of a saturated heterocyclic group of 4 to 5 members that may have a substituent), C3-C6 cycloalkyl (which may also have a substituent selected from the group consisting of hydroxyl, C1-C3 alkyl, C1-C3 alkoxy), C3-C6 cycloalkenyl, 4 to 5-membered saturated Heterocyclyl (can also have a group selected from C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy-C1-C3 alkyl, benzyl, C1-C3 alkenyl, C1-C3 Substituents composed of alkylcarbonyl, C1-C3 alkoxycarbonyl, C3-C6 cycloalkyl, 4-6 membered saturated heterocyclic group, 5-6 membered unsaturated heterocyclic group), 4~ 6-member unsaturated heterocyclic group; The substituents of A2 include hydrogen atoms, halogen atoms, cyano groups, hydroxyl groups, and C1-C6 alkyl groups; The substituents of A3 include hydrogen atoms, halogen atoms, cyano groups, nitro groups, and amino groups , hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; L ₂ represents

[Chemical formula 17]

here,

[Chemical formula 18]

Represents a 4 to 5-membered saturated heterocyclic group containing one N; R ₃ represents a hydrogen atom; n of R ₄ = 1 or 2, and represents a halogen atom, methyl, ethyl, methoxy group; L ₃ represents -C( =O); R ₅ is a C2-C6 alkenyl group which may have a substituent.

More preferably, the following compounds or salts thereof, in formula (I), X represents CH; R ₁ is a chlorine atom or a C1-C3 alkyl group with a substituent; L ₁ represents -NH-CH ₂ -; Ra is the same or different , is a hydrogen atom, a deuterium atom, or a methyl group; in terms of the combination of A1, A2, and A3 in ring A, A1 is a nitrogen atom with a substituent, A2 is a nitrogen atom, A3 is a carbon atom with a substituent, or A1 is Nitrogen atom, A2 is a sulfur atom, A3 is a carbon atom with a substituent; the substituent of A1 is a hydrogen atom, a chlorine atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tert-butyl, cyclopropyl, cyclopentyl, 3,4-dihydroxycyclopentyl, cyclohexyl, 2-isopropyl-5-methylcyclohexyl, 4-methoxycyclohexyl, cyclopentyl Alkenyl, N-tert-butoxycarbonyl ethylenepropyl, N-isopropyl ethylene, N-methylcarbonyl ethylene, N-methylpyrrolidinyl, N-ethylpyrrolidine base, N-isopropylpyrrolidinyl, N-(2,2-difluoroethyl)pyrrolidinyl, N-methylcarbonylpyrrolidinyl, N-methoxyethylpyrrolidinyl, N-benzyl A2 The substituents of A3 are hydrogen atoms, methyl, and ethyl groups; the substituents of A3 are hydrogen atoms, halogen atoms, cyano groups, C1-C6 alkyl groups, and C1-C6 haloalkyl groups; L ₂ represents

[Chemical formula 19]

here,

[Chemical formula 20]

Represents a 4~5-membered saturated heterocyclic group containing one N; R ₃ represents a hydrogen atom; R ₄ represents a halogen atom, methyl, ethyl, methoxy group; n is 0, 1 or 2; L ₃ represents -C ( =O); R ₅ is a C1-C3 alkenyl group which may have a substituent.

The most preferred compounds are _the following compounds or _their salts. In the formula (I ₎ , Deuterium atom, or methyl group; In terms of the combination of A1, A2, and A3 in ring A, A1 is a nitrogen atom with a substituent, A2 is a nitrogen atom, and A3 is a carbon atom with a substituent; the substituent of A1 is a hydrogen atom, Chlorine atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, 4-methoxycyclohexyl, N-isopropyl acridine Propidyl, N-methylpyrrolidinyl, N-isopropylpyrrolidinyl, N-(2,2-difluoroethyl)pyrrolidinyl, N-(2,2-difluoroethyl)piper Aldyl, tetrahydrofuryl, tetrahydropyranyl; The substituent of A2 is a nitrogen atom with a hydrogen atom; The substituent of A3 is methyl, ethyl, difluoromethyl, chlorine atom, fluorine atom, cyano atom; L ₂ means

[Chemical formula 21]

here,

[Chemical formula 22]

Represents a 4~5-membered saturated heterocyclic group containing one N; R ₃ represents a hydrogen atom; R ₄ represents a halogen atom, methyl, ethyl, methoxy group; n is 0, 1 or 2; L ₃ represents -C ( =O); R ₅ represents vinyl.

The compound of the present invention is preferably the following compound or a salt _thereof . In formula (I), C1-C6 alkyl group, C2-C6 alkenyl group which may also have a substituent, C2-C6 alkynyl group which may also have a substituent, C3-C10 cycloalkyl group which may also have a substituent, C6-C10 aromatic group Family hydrocarbon group, 4 to 10-membered saturated heterocyclic group or 5 to 10-membered unsaturated heterocyclic group; L ₁ represents -NH-C(Ra) ₂ -; Ra is the same or different, representing hydrogen atom, deuterium atom, C1-C6 alkyl; Ring A represents a 5-membered unsaturated heterocyclic group that may also have a substituent and has 1 to 2 heteroatoms selected from nitrogen atoms, sulfur atoms and oxygen atoms; L ₂ represents

[Chemical formula 23]

here,

[Chemical formula 24]

Represents a 4 to 8-membered saturated heterocyclic group containing at least one nitrogen atom and 0 to 2 heteroatoms selected from sulfur atoms and oxygen atoms; R ₃ represents a hydrogen atom, C1-C6 alkyl group; R ₄ represents halogen Atom, cyano group, nitro group, amine group, hydroxyl group, carboxyl group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, C1-C6 Haloalkyl, C1-C6 alkylamino-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl or C1-C6 hydroxyalkyl; L ₃ represents -C(=O)-or- S(=O) ₂ -; R ₅ represents a C2-C6 alkenyl group which may have a substituent or a C2-C6 alkynyl group which may have a substituent.

Preferred are _the following compounds or their salts. In formula (I), , or a C3-C10 cycloalkyl group that may have a substituent; L ₁ represents -NH-C(Ra) ₂ -; Ra is the same or different, and is a hydrogen atom, a deuterium atom, or a methyl group; Ring A may also have Substituent, which is formed by removing 2 hydrogen atoms from imidazole, pyrazole, thiazole or oxazole; L ₂ represents a 4-6 membered saturated heterocyclic group containing one or two N; R ₃ represents a hydrogen atom or methyl group group; n=1 or 2 in R ₄ , and represents a halogen atom, cyano group, hydroxyl group, C1-C2 alkyl group, methoxy group, C1-C2 haloalkyl group, dimethylaminomethyl or ethoxymethyl group group; L ₃ represents -C (=O); R ₅ represents a C2-C6 alkenyl group which may have a substituent or a C2-C6 alkynyl group which may have a substituent.

More preferably, the following compounds or salts thereof are: In formula (I), X represents CH; _R1 is a halogen atom, C1-C3 alkyl group, 1-propenyl group, or 2-methyl 2-propenyl group which may also have a substituent , or 1-methylcyclopropyl; L ₁ represents -NH-C(Ra) ₂ -; Ra is the same or different, and is a hydrogen atom, a deuterium atom, or a methyl group; Ring A may also have a substituent, and from A base formed by removing 2 hydrogen atoms from imidazole, pyrazole or thiazole; L ₂ represents

[Chemical formula 25]

here,

[Chemical formula 26]

Represents a 4 to 5-membered saturated heterocyclic group containing one N; R ₃ represents a hydrogen atom; n of R ₄ = 1 or 2, and represents a halogen atom, methyl, ethyl, methoxy group; L ₃ represents -C ( =O); R ₅ is a C2-C6 alkenyl group which may have a substituent.

More preferably, the following compound or a salt thereof, in the formula (I), X represents CH; R ₁ is a chlorine atom or a C1-C3 alkyl group with a substituent; L ₁ represents -NH-C(Ra) ₂ -; Ra is the same Or different, it is a hydrogen atom, a deuterium atom, or a methyl group; Ring A may also have a substituent, and is a group formed by removing two hydrogen atoms from imidazole, pyrazole, or thiazole; L ₂ represents

[Chemical formula 27]

here,

[Chemical formula 28]

Represents a 4~5-membered saturated heterocyclic group containing one N; R ₃ represents a hydrogen atom; R ₄ represents a halogen atom, methyl, ethyl, methoxy group; n is 0, 1 or 2; L ₃ represents -C ( =O); R ₅ is a C1-C3 alkenyl group which may have a substituent.

The best ones are the following compounds or their salts. In formula (I), X represents CH; R ₁ is a chlorine atom or tert-butyl group; L ₁ represents -NH-C(Ra) ₂ -; Ra is the same or different, and A hydrogen atom, a deuterium atom, or a methyl group; Ring A may have a substituent and is a group obtained by removing two hydrogen atoms from imidazole; L ₂ represents

[Chemical formula 29]

here,

[Chemical formula 30]

Represents a 4~5-membered saturated heterocyclic group containing one N; R ₃ represents a hydrogen atom; R ₄ represents a halogen atom, methyl, ethyl, methoxy group; n is 0, 1 or 2; L ₃ represents -C( =O); R ₅ represents vinyl.

Specific compounds of the present invention can be exemplified by compounds produced in the following examples, but are not limited thereto.

Suitable examples of compounds of the present invention include the following.

N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1,4-Dimethyl-1H-imidazole-5-methamide N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1-isopropyl-4-methyl-1H-imidazole-5-methamide N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-methyl-1H-imidazole-5-methamide N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-(difluoromethyl)-1-isopropyl-1H-imidazole-5-methamide N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-isopropyl-1H-imidazole-5-methamide N-((3S,4S)-1-propenyl-4-fluoropyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole-3) -(yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide N-((3S,4S)-1-propenyl-4-fluoropyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole-3) -yl)amino)methyl)-4-fluoro-1-methyl-1H-imidazole-5-carboxamide N-((3S,4S)-1-propenyl-4-fluoropyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole-3) -yl)amino)methyl)-4-chloro-1-methyl-1H-imidazole-5-carboxamide N-((3R,4R)-1-propenyl-4-methylpyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole- 3-yl)amino)methyl)-4-chloro-1-methyl-1H-imidazole-5-carboxamide N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-(difluoromethyl)-1-(1-isopropylpyrrolidin-3-yl)-1H-imidazole-5-methamide (S)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-methamide N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(tetrahydro-2H-piran-4-yl)-1H-imidazole-5-methamide (R)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-methamide N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(1-methylpiperidin-4-yl)-1H-imidazole-5-carboxamide N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(tetrahydro-2H-piran-3-yl)-1H-imidazole-5-methamide N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-cyclopentyl-1H-imidazole-5-methamide tert-butyl 3-(5-((1-propenyl azetidin-3-yl)aminomethanoyl)-2-(((5-(tert-butyl)-6-chloro-1H- Indazol-3-yl)amino)methyl)-4-chloro-1H-imidazol-1-yl)azetidine-1-carboxylate N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(1-isopropylazetidin-3-yl)-1H-imidazole-5-methamide N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(4-methoxycyclohexyl)-1H-imidazole-5-carboxamide (R)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-1H-imidazole-5-methamide (R)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(1-isopropylpyrrolidin-3-yl)-1H-imidazole-5-methamide (S)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-1H-imidazole-5-methamide (R)-N-(1-propenyl azedine-3-yl)-1-(1-allylpyrrolidin-3-yl)-2-((5-(tert-butyl) -6-Chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1H-imidazole-5-carboxamide (R)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(1-(pyridin-2-yl)pyrrolidin-3-yl)-1H-imidazole-5-methamide N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-((3R,5R)-1-(2,2-difluoroethyl)-5-methylpyrrolidin-3-yl)-1H-imidazole-5-carboxamide

Next, a method for producing the compound of the present invention will be described. The compound represented by formula (I) of the present invention can be produced by, for example, the following production method or the method shown in the Examples. However, the method for producing the compound represented by formula (I) of the present invention is not limited to these reaction examples. The products obtained in each step can be separated and purified by well-known separation and purification methods, such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or they can be delivered without separation and purification. Go to next step. The products and raw materials obtained in each step may be optionally introduced with a protecting group that can be easily converted into the functional group, thereby making each step effective or replacing each step. The protective group that can be used here can be used, for example, the method described in the literature [Greene and Wuts, "Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc, 2014] Protective groups, etc., can be appropriately selected according to the reaction conditions used in each step. After introducing the protecting group and carrying out the reaction, if necessary, the protecting group can be removed to obtain the desired compound.

General manufacturing method 1

[Chemical formula 31]

[In the formula, PG ₁ represents a hydrogen atom, an amine protecting group, or -L ₃ -R ₅ . R _a represents a hydrogen atom or a deuterium atom, and A, L ₂ , L ₃ and R ₅ have the same meanings as above. ] is a step for producing a compound represented by formula (V-1). Compound (II) and compound (III) are submitted to the amide reaction in step A to obtain compound (IV), and then the formamide is submitted to step B. chemical reaction to obtain a compound represented by formula (V-1).

Step A is carried out by using 0.5 to 10 moles, and preferably 1 to 3 moles of compound (III) per mole of compound (II). In a solvent that is inactive for the reaction, add an appropriate condensing agent as the amide reagent, and stir from cooling to heating, preferably from -20°C to 80°C, usually for 1 minute to 1 week. Examples of the condensation agent that can be used here are not particularly limited, and examples include N,N'-dicyclohexylcarbodiamide, N,N'-diisopropylcarbodiimide, 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazole -1-yloxy-shen-(dimethylamino)phosphonium hexafluorophosphate, benzotriazole-1-yloxy-shen-pyrrolidinylphosphonium hexafluorophosphate, bromoshen-(dimethyl Amino)phosphonium hexafluorophosphate, diphenylphosphate azide, 1,1'-carbonyldiimidazole, etc. Examples of solvents that can be used here are not particularly limited, and may include toluene, methylene chloride, chloroform, THF, 1,4-dioxane, DMF, N,N-dimethylacetamide, NMP, 2 -Propanol, ethanol, methanol, water, etc. and their mixtures. Moreover, if necessary, additives such as 1-hydroxybenzotriazole and alkali may be added. Examples of the base are not particularly limited, and examples thereof include inorganic bases such as sodium carbonate, potassium carbonate, and sodium bicarbonate, triethylamine, N,N diisopropylethylamine, and 4-dimethylamino Pyridine and other organic bases and their mixtures.

In step B, a generally well-known reaction for introducing a formyl group can be used. For example, applicable methods include: (1) a method of using a strong base to generate anions and reacting with a formate; (2) a method of using formaldehyde, etc. to perform hydroxymethylation, and using an oxidizing agent such as manganese dioxide to convert it into a formate group. ; (3) After halogenation, perform halogen-metal exchange using an alkyl metal reagent and react with a formate; (4) After halogenation, introduce vinyl through a coupling reaction and then oxidatively crack the vinyl, etc. This reaction can be carried out by adding a strong base to an appropriate solvent, for example, and stirring in the range from -78°C to room temperature, usually for 10 minutes to 12 hours, thereby generating anions, and adding a formate. The reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction, and examples thereof include ethers such as tetrahydrofuran and 1,4-dioxane, hydrocarbons such as benzene and toluene, and mixtures thereof. Examples of strong bases that can be used here are not particularly limited, and examples include butyllithium, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine (lithium 2,2,6,6- tetramethylpiperidide), 2,2,6,6-tetramethylpiperidyl magnesium chloride lithium chloride complex, etc. Examples of the formate reagent that can be used here are not particularly limited, and examples include N, N-dimethylformamide, ethyl formate, and the like.

General manufacturing method 2

[Chemical formula 32]

[In the formula, A, L ₂ , PG ₁ , R _a , R ₁ , R ₂ and X are synonymous with the above. ] A step of producing a compound represented by formula (VII) by subjecting compound (V-1) and compound (VI) to a reductive amination reaction in step C.

Step C is carried out by using 0.5 to 10 moles, preferably 0.5 to 2 moles of compound (VI) per mole of compound (V-1). The reaction can also be carried out using a reducing agent in a solvent suitable for the reaction, and if necessary, additives can also be added. Solvents, such as toluene, methylene chloride, chloroform, ethyl acetate, THF, 1,4-dioxane, N.N-dimethylformamide, N-methylpyrrolidone, DMSO, methanol, ethanol , 2-propanol, tert-butyl alcohol, etc. or mixed solvents thereof are suitable. Examples of the reducing agent that can be used here are not particularly limited, and examples include hydride metal complexes, such as sodium borohydride, sodium cyanoborohydride, and triacetyloxy hydride in 0.1 mol to a large excess. Boron hydrogen, etc. Examples of additives that can be used here are not particularly limited and may include acids, bases, inorganic salts or organic salts, such as 0.01 mol to a large excess of trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, potassium carbonate, sodium hydroxide, Lithium hydroxide, sodium sulfate, magnesium sulfate, tetraisopropyl orthotitanate, etc.

General manufacturing method 3

[Chemical formula 33]

[In the formula, X ₁ represents a leaving group. In the formula, A, L ₂ , PG ₁ and R _a are synonymous with the above. ] A step of producing a compound represented by formula (V-2) by subjecting compound (VIII) to halogenation in step D, or by introducing a leaving group in step E into compound (IX).

Step D can be carried out using N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine, iodine, etc. The solvent is not particularly limited as long as it does not hinder the reaction. For example, acetonitrile, ethyl acetate, THF, methanol, ethanol, DMF, N,N-dimethylacetamide, NMP, chloroform, carbon tetrachloride, etc. can be used. Proceed in an appropriate solvent that would hinder the reaction. The reaction temperature is usually 0°C to 100°C, and preferably room temperature to reflux temperature. The reaction time is usually 10 minutes to 3 days, and preferably 30 minutes to 24 hours.

The method of introducing the leaving group in step E is not particularly limited. For example, the conditions for sulfonyl esterification include conditions using methane sulfonyl chloride, toluene sulfonyl chloride, etc. and an appropriate base. Examples of conditions for halogenation include conditions using a halogenating agent such as carbon tetrachloride, carbon tetrabromide, or iodine, and triphenylphosphine, or the like, or treating the aforementioned sulfonyl ester with lithium halide or the like to convert it into a halogenated ester. conditions.

General manufacturing method 4

[Chemical formula 34]

[In the formula, A, L ₂ , PG ₁ , R _a , R ₁ , R ₂ , X and X ₁ are synonymous with the above. ] A step of producing a compound represented by formula (VII) by subjecting compound (V-2) and compound (VI) to an alkylation reaction in step F.

Step F is carried out by using 0.5 to 10 moles, preferably 1 to 3 moles of compound (VI) per mole of compound (V-2). Solvents, such as toluene, methylene chloride, chloroform, THF, 1,4-dioxane, DMF, N-methylpyrrolidone, DMSO, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, etc. Or its mixed solvent is more suitable. Examples of the base that can be used here include inorganic bases such as sodium bicarbonate, potassium carbonate, cesium carbonate and potassium hydroxide, or potassium-tert-butyric acid, sodium-tert-butyric acid, sodium methoxide, sodium ethoxide, Organic bases such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, triethylamine, N,N-diisopropylethylamine, etc.

General manufacturing method 5

[Chemical formula 35]

[In the formula, A, L ₂ , L ₃ , PG ₁ , R _a , R ₁ , R ₂ , R ₅ and X are synonymous with the above. ] When PG ₁ is the protecting group of amine, compound (VII) is submitted to the deprotection reaction of step G to obtain compound (X), and then submitted to the amidation reaction of step H to produce the compound of formula (I). Show the steps for the compound. When PG1 is a hydrogen atom, the reaction is carried out to the amidation reaction in step H to produce the compound represented by formula (I). The amine protecting group that can be used here is not particularly limited, and examples thereof include tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

Step G varies depending on the type of protective group. For example, the method described in the literature [Greene and Wuts, "Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc, 2014 ] or a method based thereon, such as solvolysis using acid or alkali, that is, for example, using 0.01 mol to a large excess of acid, preferably trifluoroacetic acid, formic acid, hydrochloric acid, etc., or using Methods using molar to large excess of alkali, preferably sodium hydroxide, lithium hydroxide, etc.; chemical reduction using hydrogenation metal complexes, etc. or contact reduction using palladium carbon catalysts, Raney nickel catalysts, etc. Wait to proceed.

Step H is to use 0.5 to 10 moles of a chelation reagent for 1 mole of the compound (X) obtained in the previous step, and add the mixture to a solvent inactive for the reaction in the presence of a base. Cooling to heating, preferably from -20°C to 80°C, usually stirring for 3 days starting from the completion of adding the chelation reagent. Examples of solvents that can be used here are not particularly limited, and examples include ethers such as THF, diethyl ether, 1,4-dioxane, and 1,2-dimethoxyethane, dichloromethane, 1,2-dimethoxyethane, and the like. Halogenated hydrocarbons such as ethyl chloride and chloroform, alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene, toluene and xylene, DMF, DMSO, ethyl acetate, acetonitrile, water and mixtures thereof. Examples of bases that can be used here include inorganic bases such as sodium carbonate, potassium carbonate, and sodium bicarbonate; organic bases such as triethylamine and N,N-diisopropylethylamine; and mixtures thereof. Examples of the chelating reagent include acid halide compounds and acid anhydrides. Examples of acid halide compounds include acryl chloride and the like. Alternatively, the following method can be used: for 1 mol of compound (X), 0.5 to 10 mol, preferably 1 to 3 mol of carboxylic acid is used, and the mixture is inactive for the reaction in the presence of a condensing agent. In the solvent, in the presence of a base if necessary, from cooling to heating, preferably -20°C to 80°C, usually stirring for 1 minute to 3 days. Examples of the condensing agent are not particularly limited, and examples thereof include N,N'-dicyclohexylcarbodiamide, N,N'-diisopropylcarbodiimide, and 1-(3-dimethylamine). Propyl)-3-ethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazole-1-yl Oxy-shen-(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxy-shen-pyrrolidinylphosphonium hexafluorophosphate, bromo-shen-(dimethylamino) Phosphonium hexafluorophosphate, diphenylphosphate azide, 1,1'-carbonyldiimidazole, etc. Examples of solvents that can be used here are not particularly limited, and examples include toluene, methylene chloride, chloroform, THF, 1,4-dioxane, DMF, N,N-dimethylacetamide, NMP, 2- Propanol, ethanol, methanol, water, etc. and their mixtures. Moreover, if necessary, additives such as alkali may be added. Examples of the base are not particularly limited, and examples thereof include inorganic bases such as sodium carbonate, potassium carbonate, and sodium bicarbonate, or triethylamine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine. and other organic bases and their mixtures.

General manufacturing method 6

[Chemical formula 36]

[In the formula, X ₂ represents a halogen atom, PG ₂ represents the protecting group of ester, and A, R _a and X ₁ have the same meaning as above. ]

By using generally well-known reactions from commercially available aromatic cyclic esters or aromatic cyclic esters that can be synthesized by well-known methods, formula (XII-1) or formula (XII-2) can be produced Procedure for the compounds shown.

For example, the formula (XII-1) can be exemplified by the following method: (1) The halogen atom of the formula (XI-1) is vinylated by cross-coupling or the like through a compound represented by the formula (XI-2), and then a catalyst is used An amount of osmium tetroxide and an excess of sodium periodate are used to cut off the double bond; (2) Use Grenya reagent, butyl lithium, etc. to carry out halogen-metal analysis of the halogen atoms of formula (XI-1). A method of exchanging and reacting with a formiculating agent or a chelating agent; (3) A method of using a strong base to generate an anion in formula (XI-3) and reacting with a formiculating agent or a chelating agent, Or the method of formylation using the Viersmeier reaction; (4) the method of reducing the ester of formula (XI-4); (5) the method of oxidizing the hydroxymethyl group of formula (XI-5), etc. . In addition, formula (XII-2) can be exemplified by the following method: (6) reacting the ester of formula (XI-4), ketone, aldehyde, etc. of formula (XII-1) with a reducing agent; or (7) by reacting the formula ( The ketones and aldehydes of XII-1) use alkyl metal reagents such as Grenzier reagents, and then pass through the compound represented by formula (XI-5), introducing a methane sulfonyl group or replacing it with a halogen atom; or (8) Methods such as halogenating the methylene group of formula (XI-6) with N-bromosuccinimide or the like.

General manufacturing method 7

[Chemical formula 37]

[In the formula, A, L ₂ , L ₃ , PG ₂ , R _a , R ₁ , R ₂ , R ₅ , X and X ₁ are synonymous with the above. ] After the compound (XIII) is obtained by subjecting the compound (XII-1) to the aforementioned step C, or subjecting the compound (XII-2) to the aforementioned step F, the compound (XIII) is deprotected in step I and delivered to the aforementioned step A. , a step whereby a compound represented by formula (I) is produced.

Step I can apply a hydrolysis reaction method of carboxylic acid esters known in the field of organic chemistry, and is not particularly limited. It can be carried out by, for example, solvolysis using an acid or a base, for example, using 0.01 mol to a large excess of acid. , preferably trifluoroacetic acid, formic acid, hydrochloric acid, etc., or a method of making an equimolar to large excess of alkali, preferably sodium hydroxide, lithium hydroxide, etc.

General manufacturing method 8

[Chemical formula 38]

[In the formula, X ₃ represents a substituent that can be converted into a cyano group or the like. Examples thereof include halogen, amine, ester, amide, carboxylic acid, and the like. X ₄ represents a substituent convertible into hydrazine or the like. Examples include protected forms of halogen, amine, and hydrazine. R ₁ , R ₂ and X are synonymous with the above. ]

Compound (XVI), which can be obtained by a well-known method, is subjected to the cyanolation reaction in step J to obtain compound (XVII), and then is subjected to the indazole cyclization reaction in step K to produce the formula (VI). ) steps for the compound shown.

Step J is a method of introducing a cyano group by a method known in the field of organic chemistry. For example, when X ₃ of formula (XVI) is an amine group, in an appropriate solvent in the range from -20°C to room temperature, A diazotizing agent is added to prepare a diazonium salt, and the obtained diazonium salt is added to a solution of an alkali and a cyanating agent in a temperature range from -20°C to 100°C. Usable reaction solvents include acidic solvents such as hydrochloric acid, acetic acid, trifluoroacetic acid and sulfuric acid, alcohols such as methanol and ethanol, water and mixtures thereof. Examples of diazotizing agents include sodium nitrite, isoamyl nitrite, etc. Examples of bases include sodium hydroxide, sodium carbonate, sodium bicarbonate, etc. Examples of cyanating agents include sodium cyanide, potassium cyanide, copper cyanide, zinc cyanide, and mixtures thereof. For example, when X ₃ in formula (XVI) is a halogen atom, a cyanating agent can also be used, and the process can be carried out in a suitable solvent in the range from room temperature to 200°C. In addition, a palladium catalyst or the like may be added as an additive during the reaction. Examples of cyanating agents include sodium cyanide, potassium cyanide, copper cyanide, zinc cyanide, and mixtures thereof. The reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction. Examples include ethers such as THF and 1,4-dioxane, alcohols such as methanol and ethanol, DMF, N,N-dimethylacetamide, Amides such as N-methyl-2-pyrrolidone, hydrocarbons such as toluene, acetonitrile, dimethylstyrene, water, or mixed solvents thereof.

Step K, for example, when X ₄ in formula (XVII) is halogen, hydrazine or the like can be reacted in a suitable solvent in a range from 20°C to 200°C. Alternatively, hydrazine protected by a protecting group may be subjected to a cross-coupling reaction using a palladium catalyst, and then the protecting group of hydrazine may be deprotected. The reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction. Examples include ethers such as THF and 1,4-dioxane, alcohols such as methanol and ethanol, DMF, N,N-dimethylacetamide, Amides such as N-methyl-2-pyrrolidinone, hydrocarbons such as toluene, acetonitrile, dimethylstyrene, water, or mixed solvents thereof. Examples of palladium catalysts that can be used include palladium acetate, palladium chloride, palladium quaternary (triphenylphosphine), dichlorobis(triphenylphosphine)palladium, dichloro(1,1'-bis(diphenylphosphine) )Palladium, dichlorobisacetonitrile palladium, ginseng (dibenzylideneacetone) dipalladium (0). The amount of the palladium catalyst that can be used is appropriately in the range of 0.001 to 1 mole relative to 1 mole of the compound represented by formula (XVII). If necessary, 1-1'-bis(diphenylphosphino)ferroxin and 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene can be used as the palladium ligand. , 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-di- tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl, etc. Examples of the base in this step include potassium-tert-butyric acid, sodium-tert-butyric acid, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, and hexamethyldisilazide. Organic bases such as sodium and potassium hexamethyldisilonitriol, or inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium phosphate, and potassium phosphate. Although it varies depending on the reaction temperature, it is usually within the range of 30 minutes to 24 hours. The deprotection of the protecting group of hydrazine varies depending on the protecting group used, and can be deprotected according to the method described in the literature [Greene and Wuts, "Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc, 2014] or the method thereof shall prevail.

When a compound of the present invention has isomers such as optical isomers, stereoisomers, rotamers, and tautomers, any isomers or mixtures are included in the compounds of the present invention unless otherwise specified. For example, when an optical isomer exists in a compound of the present invention, unless otherwise noted, the racemate and the optical isomer separated from the racemate are included in the compound of the present invention.

The compound of the present invention or its salt may be amorphous or crystalline, and even a single crystal form or a polymorphic mixture is included in the compound of the present invention or its salt. Crystals can be produced by crystallization using a well-known crystallization method. The compound of the present invention or a salt thereof may be a solvate (such as a hydrate, etc.) or an unsolvated compound, and both are included in the compound of the present invention or a salt thereof. Compounds labeled with isotopic elements (such as ² H, ³ H, ¹³ C, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) are also included in the compounds of the present invention or their salts.

The salt of the compound of the present invention means a pharmaceutically acceptable salt, and examples thereof include a base addition salt or an acid addition salt.

The compounds of the present invention or salts thereof also include prodrugs thereof. A prodrug refers to a compound that is converted into the compound of the present invention or its salt through the reaction of enzymes, gastric acid, etc. under physiological conditions in the body. That is, enzymatic oxidation, reduction, hydrolysis, etc. occur to change the compound of the present invention or its salt. The compound of its salt is converted into the compound of the present invention or its salt by hydrolysis by gastric acid or the like. Alternatively, the compound of the present invention or its salt may be modified under physiological conditions as described in "Development of Pharmaceuticals", Volume 7, Molecular Design, 1990, Guangchuan Bookstore, page 163 to page 198.

When the compound of the present invention or its salt is used as medicine, it may be blended with pharmaceutical carriers as necessary, and may be administered in various forms according to the purpose of prevention or treatment. The form may be, for example, oral administration, injection, suppository, or ointment. Any form such as tablets, inhalants, patches, etc. Such administration forms can be produced using various formulation methods commonly used by those skilled in the art.

Pharmaceutically acceptable carriers can use various organic or inorganic carrier substances commonly used in preparation materials. They can be blended as excipients, binding agents, disintegrating agents, lubricants, and colorants in solid preparations, and can be blended as liquids. The solvent, cosolvent, suspending agent, isotonic agent, buffering agent, analgesic agent, etc. in the preparation can be blended. In addition, preparation additives such as preservatives, antioxidants, colorants, sweeteners, and stabilizers may also be used as necessary.

When preparing a solid preparation for oral use, excipients are added to the compound of the present invention, and if necessary, a binding agent, a disintegrating agent, a lubricant, a coloring agent, a flavoring and an odor improving agent, etc. may be added, and then tablets and coated tablets may be produced in a conventional manner. Agents, granules, powders, capsules, etc.

When preparing an injection, a pH adjuster, a buffer, a stabilizer, an isotonic agent, and a local anesthetic can be added to the compound of the present invention, and injections for intramuscular and intravenous use can be prepared in a conventional manner.

The amount of the compound of the present invention that should be blended in each of the above-mentioned dosage unit forms may vary depending on the symptoms of the patient to whom it is applied or the dosage form, etc. However, generally speaking, in each dosage unit form, The dosage is preferably about 0.05 to 1000 mg for oral dosage forms, about 0.01 to 500 mg for injection dosage forms, and about 1 to 1000 mg for suppository dosage forms.

In addition, the dosage per day of a drug having the above-mentioned administration form varies depending on the patient's symptoms, weight, age, gender, etc., and cannot be determined uniformly. However, for the compound of the present invention, the dosage per day for an adult (body weight 50 kg) is usually It should be about 0.05~5000mg per day, preferably 0.1~1000mg.

The compound of the present invention or its salt has excellent KRAS inhibitory activity against KRAS G12C mutation-positive cancer cells. In addition, it has excellent selectivity for wild-type KRAS in normal cells. Therefore, the compound of the present invention or its salt is useful as an anti-tumor agent against KRAS G12C mutation-positive cancer cells and has the advantage of having few side effects.

The compound of the present invention or its salt induces functional inhibition of KRAS through excellent G12C blocking activity of KRAS, and is useful as a medicine for preventing and/or treating diseases in which KRAS-related information is involved.

One aspect of the present invention is to administer a compound of the present invention or a salt thereof in combination with an effective amount of one or more other anti-tumor agents, thereby preventing and/or treating diseases (especially tumors) in which KRAS-related information is involved.

The so-called "diseases in which KRAS-related messages are involved" refer to RAS-related messages. KRAS is related to various message transmissions. Although there is no particular limit, as the main ones that activate KRAS, RAF, PI3K, RAL- GEF et al. Examples include diseases that reduce the incidence, alleviate symptoms, alleviate and/or recover by removing, inhibiting and/or hindering these functions. Examples of such diseases include cancer, autoimmune diseases, macroglobulinemia, etc., but are not limited thereto. Tumors targeted by the present invention are not particularly limited, and examples include head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder, bile duct cancer, etc.), pancreatic cancer, and colorectal cancer). Cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, genital cancer (ovarian cancer, uterine cancer (cervix cancer, uterine corpus cancer, etc.), etc.) ), urinary cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumors, etc.), hematopoietic organ tumors (leukemia, malignant lymphoma, multiple bone marrow tumors, etc.), bone and soft part tumors, skin cancer, brain tumors, etc. Lung cancer, pancreatic cancer, and colorectal cancer are preferred.

[Example] Examples and test examples are shown below to further explain the present invention in detail. However, the present invention is not limited to these examples. Various reagents used in the examples were commercially available unless otherwise noted. Silica gel column chromatography and alkaline silicone column chromatography use pre-packed columns manufactured by Illumination Scientific or Biotage. The NMR spectrum uses an AL400 (400MHz; JEOL) or Mercury400 (400MHz; Varian) type spectrometer. When the heavy solvent contains tetramethylsilane, tetramethylsilane is used as the internal reference. In addition, is measured using NMR solvent as an internal reference, with full delta values shown in ppm. The microwave reaction was performed using Initiator (registered trademark) manufactured by Biotage. The meaning of the abbreviations is shown below. s: single peak d: Twin Peaks t: three peaks q: four peaks sep：seventh peak dd: double twin peaks dt: double triple peak td: triple twin peaks tt: triple triple peak ddd: double double double peaks ddt: double double triple peak dtd: double triple twin tdd: triple double twin peaks m: multiple peaks br: broad peak brs: broad single peak tert: level three DMSO-d 6: heavy dimethyl sulfoxide CDCl 3: heavy chloroform CD3OD: heavy methanol THF: Tetrahydrofuran DMF: N,N-dimethylformamide NMP: 1-methyl-2-pyrrolidinone DMSO: dimethylsulfoxide WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate Boc: tert-butoxycarbonyl Manufacturing example 1 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (Step 1) Under ice cooling, nitric acid (1.40) (23 mL) was slowly added to concentrated sulfuric acid (32 mL), and then 1-bromo-4-tert-butylbenzene (60 g) was added at an internal temperature of 25°C or lower. After stirring at room temperature for 3 hours, ice was added, and the mixture was extracted with diethyl ether. The organic layer was washed with aqueous sodium bicarbonate solution and saturated brine, and dried over sodium sulfate. The solution was distilled off under reduced pressure to obtain crude 1-bromo-4-(tert-butyl)-2-nitrobenzene (72.1 g). (Step 2) Divide the crude 1-bromo-4-(tert-butyl)-2-nitrobenzene (72.1g), iron powder (50g) and ammonium chloride (50g) obtained in the above step 1 into ethanol ( 400 mL) and water (100 mL) suspension was stirred at 70°C for 90 minutes. After ethanol was distilled off under reduced pressure, water and ethyl acetate were added, and insoluble matter was filtered off. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and ethyl acetate (200 mL) and acetic anhydride (30 mL) were added. The solvent was distilled off under reduced pressure, hexane (300 mL) was added, and the precipitated solid was collected to obtain N-(2-bromo-5-(tert-butyl)phenyl)acetamide (40.6 g). (Step 3) For N-(2-bromo-5-(tert-butyl)phenyl)acetamide (5.40g) and (D)-(+)-10-camphorsulfonic acid obtained in the above step 2 (2.40g), N-chlorosuccinimide (4.00g) was added to a solution of 1,3-dimethylimidazolidinium chloride (264mg) in 1,4-dioxane (54mL), and stirred at room temperature. all night. Aqueous sodium bicarbonate solution and sodium thiosulfate were added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The mixture was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained solid was collected to obtain N-(2-bromo-5-(tert-butyl)-4-chlorophenyl)acetamide (5.40 g). (Step 4) Add 5N hydroxide to a solution of N-(2-bromo-5-(tert-butyl)-4-chlorophenyl)acetamide (17.1 g) obtained in step 3 above in ethanol (100 mL). aqueous sodium solution (100 mL) and stirred at 90°C for 5 hours. The ethanol in the reaction solution was distilled off under reduced pressure, extracted with 2-methyltetrahydrofuran, and the organic layer was washed with saturated brine. The mixture was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2-bromo-5-(tert-butyl)-4-chloroaniline (14.8 g). (Step 5) Cool the 2-bromo-5-(tert-butyl)-4-chloroaniline (81.1 g) obtained in the above step 4 to the internal temperature of 0°C, and add 3N hydrochloric acid (566 mL). Sodium nitrite (24.3g) was added little by little, and the mixture was stirred at an internal temperature of 0° C. for 1 hour to prepare a diazonium salt suspension. To a suspension of copper (I) cyanide (27.7g), sodium cyanide (30.3g), and sodium bicarbonate (145g) in water (570mL), under ice-cooling, add a diazonium salt suspension, and incubate at 0°C. Stir for 1 hour. After stirring, the temperature was raised to room temperature, ethyl acetate was added, and the mixture was filtered through diatomaceous earth. The filtrate was separated, the organic layer was washed with 20% brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography purification (hexane: ethyl acetate) to obtain 2-bromo-5-(tert-butyl)-4-chlorobenzonitrile (61.1 g). (Step 6) 2-bromo-5-(tert-butyl)-4-chlorobenzonitrile (61.1g), benzophenone hydrazone (51.9g), and rac-2,2 obtained in the above step 5 To a suspension of '-bis(diphenylphosphino)-1,1'-binaphthyl (7.7g) and cesium carbonate (102g) in toluene (470mL), palladium acetate (2.5g) was added, and under nitrogen atmosphere, Heating at internal temperature 101°C for 1.5 hours. Cool to room temperature, add ethyl acetate and water, filter through diatomaceous earth, and separate the organic layer. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane: dichloromethane), thereby obtaining 5-(tert-butyl)-4-chloro-2-(2-(diphenylmethylene)hydrazino) Benzonitrile (52.8g). (Step 7) Methanol (52.8 g) of 5-(tert-butyl)-4-chloro-2-(2-(diphenylmethylene)hydrazino)benzonitrile (52.8 g) obtained in the above step 6 375 mL) p-toluenesulfonic acid monohydrate (51.8 g) was added to the solution, and heated at an internal temperature of 63°C for 1.5 hours. Cool to room temperature and wash with hexane. The hexane layer was extracted with methanol, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, and washed with a mixed solution of saturated sodium bicarbonate aqueous solution (375 mL) and 5N sodium hydroxide aqueous solution. The aqueous layer was washed with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution. It was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography purification (hexane: ethyl acetate) to obtain the title compound (29.0 g).

Manufacturing example 2 6-Chloro-5-vinyl-1H-indazole-3-amine (Step 1) Pyridine (100 mL) and acetic anhydride (30 mL) were added to 3-amino-6-chloro-1H-indazole (15.1 g), and the mixture was stirred at room temperature over the weekend. The reaction solution was concentrated, and methanol (300 mL) and 5N sodium hydroxide aqueous solution (70 mL) were added and stirred for 1 hour. The reaction solution was concentrated and neutralized with 10% phosphoric acid aqueous solution. The solid obtained was collected and washed with water. After drying the collected solid, N-(6-chloro-1H-indazol-3-yl)acetamide (15.1 g) was obtained. (Step 2) To the solution of N-(6-chloro-1H-indazol-3-yl)acetamide (4.20 g) obtained in the above step 1 in THF (20 mL) and DMF (10 mL), N-bromosuccinate was added Imide (3.90g), stir for 1 hour. Water was added to the reaction liquid, THF was distilled off, and the solid was collected. It was dried under reduced pressure at 50° C. to obtain N-(5-bromo-6-chloro-1H-indazol-3-yl)acetamide (4.76 g). (Step 3) To the methanol (100 mL) suspension of N-(5-bromo-6-chloro-1H-indazol-3-yl)acetamide (4.76 g) obtained in the above step 2, concentrated hydrochloric acid (10 mL ) and stir at 70°C for 2 hours. The reaction liquid was concentrated, water was added to the obtained residue, and the obtained solid was collected. It was dried under reduced pressure at 70° C. to obtain 5-bromo-6-chloro-1H-indazole-3-amine hydrochloride (4.06 g). (Step 4) Use 5-bromo-6-chloro-1H-indazol-3-amine hydrochloride (282 mg) and 4,4,5,5-tetramethyl-2-ethenyl obtained in the above step 3. -1,3,2-dioxaborane (300μL), 4-triphenylphosphine palladium (0) (120mg), 2M aqueous sodium carbonate solution (1.5mL) in 1,4-dioxane (4.5mL) The suspension was stirred at 100°C for 13 hours. Ethyl acetate and water were added to the reaction solution, the organic layer was separated, and the organic layer was washed with saturated brine. The residue was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform:ethanol) to obtain the title compound (164 mg).

Manufacturing example 3 6-Chloro-5-ethyl-1H-indazole-3-amine To a solution of 6-chloro-5-vinyl-1H-indazol-3-amine (135 mg) obtained in Production Example 2 in THF (1.0 mL) and ethanol (1.0 mL), rhodium carbon was added under a nitrogen atmosphere. (Rh5%) (100mg), replace the reaction system with hydrogen, and stir for 5 days. Replace the reaction system with nitrogen and filter the reaction solution. The solvent was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:ethanol), thereby obtaining the title compound (31 mg).

Manufacturing example 4 5-(tert-butyl)-6-chloro-1H-pyrazolo[4,3-b]pyridin-3-amine (Step 1) N-chlorosuccinimide (620 mg) and chloroform (5.0 mL) were added to 6-(tert-butyl)pyridin-2-ol (291 mg), and the mixture was stirred at room temperature for 1 hour. Acetic acid (5.0 mL) was added to the reaction liquid, and the mixture was stirred at 50° C. overnight. The reaction solution was concentrated, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining 6-(tert-butyl)-3,5-dichloropyridin-2-ol (386 mg) . (Step 2) To 6-(tert-butyl)-3,5-dichloropyridin-2-ol (386 mg) obtained in the above step 1, add toluene (10 mL), phosphorus oxybromide (400 mg), and DMF (12 μL) and stirred at 100°C for 18 hours. DMF (30 μL) was added and stirred at 120°C for 9 hours. Ethyl acetate, water, and sodium bicarbonate aqueous solution were added to the reaction liquid, and the organic layer was separated. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining 2-bromo-6-(tert-butyl)-3,5- Dichloropyridine (155 mg). (Step 3) Suspend 2-bromo-6-(tert-butyl)-3,5-dichloropyridine (155 mg) and copper (I) cyanide (100 mg) obtained in the above step 2 in NMP (2 mL) The solution was stirred at 120°C for 2 hours. The reaction liquid was cooled to room temperature, ethyl acetate and concentrated ammonia water were added to the reaction liquid, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining 6-(tert-butyl)-3,5-dichlorocyanopyridine. (111mg). (Step 4) Add hydrazine monohydrate (300 μL) to the 2-propanol (1.5 mL) solution of 6-(tert-butyl)-3,5-dichlorocyanopyridine (105 mg) obtained in the above step 3. And use a microwave reaction device to react at 120°C for 12 hours. Hydrazine monohydrate (300 μL) was added and further reacted at 130° C. for 6 hours. The reaction solution was purified by column chromatography (chloroform:ethanol) to obtain the title compound (42 mg).

Manufacturing example 5 6-Chloro-5-methyl-1H-indazole-3-amine (Step 1) A sodium bicarbonate aqueous solution was added to 5-bromo-6-chloro-1H-indazol-3-amine hydrochloride (110 mg) obtained in Production Example 2 (Step 3), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 5-bromo-6-chloro-1H-indazol-3-amine (63.9 mg). (Step 2) Prepare 5-bromo-6-chloro-1H-indazol-3-amine (37 mg), methylboronic acid (30 mg), and (1,1'-bis(diphenylphosphine) obtained in step 1 above. (12mg), 0.5M 3 potassium phosphate aqueous solution (1.0mL), 1,4-dioxane (1.0mL), and at 100°C Stir overnight. Methylboric acid (30 mg) and 0.5 M potassium phosphate aqueous solution (1.0 mL) were added, and the mixture was further stirred overnight. Ethyl acetate and water were added to the reaction solution to separate the layers, and the organic layer was washed with saturated brine. The residue was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform:ethanol) to obtain the title compound (10.8 mg).

Manufacturing example 6 5-(tert-butyl)-6-methyl-1H-indazole-3-amine (Step 1) Acetic anhydride (7.0 mL) was added to a solution of 3-tert-butylaniline (10 g) in ethyl acetate (100 mL), and the mixture was concentrated under reduced pressure. To the obtained residue were added 1,4-dioxane (150 mL), 1,3-bis(1-adamantyl)-1H-imidazolidinium tetrafluoroborate (500 mg), and D-(+)-10- Camphorsulfonic acid (7.80g), N-chlorosuccinimide (9.50g), and stirred at room temperature for 8 hours. The reaction solution was concentrated, ethyl acetate and saturated sodium bicarbonate aqueous solution were added to the obtained residue, and the organic layer was separated. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography purification (hexane: ethyl acetate) to obtain N-(3-(tert-butyl)-4-chlorophenyl)acetamide (9.19g) and N -(5-(tert-butyl)-2-chlorophenyl)acetamide (4.14g). (Step 2) Use N-(5-(tert-butyl)-2-chlorophenyl)acetamide (1.13g), N-bromosuccinimide (1.00g), and acetic acid obtained in the above step 1. (10 mL) solution was stirred at 60°C overnight. N-bromosuccinimide (800 mg) was added, and the mixture was further stirred at 60°C for 5 hours. The reaction liquid was concentrated under reduced pressure, and an aqueous sodium bicarbonate solution and sodium thiosulfate were added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. Dry with sodium sulfate, remove the solvent by distillation under reduced pressure, and subject the obtained residue to column chromatography purification (hexane: ethyl acetate), thereby obtaining N-(4-bromo-5-(tert -Butyl)-2-chlorophenyl)acetamide (1.11 g). (Step 3) To N-(4-bromo-5-(tert-butyl)-2-chlorophenyl)acetamide (966 mg) obtained in the above Step 2, add (1,1'-bis(diphenyl) Phosphino)ironium)palladium (II) dichloride dichloromethane adduct (200 mg), 1,4-dioxane (12 mL), dimethyl zinc (2M toluene solution, 3.50 mL), at 100 Stir for 90 minutes at ℃. The reaction solution was cooled to room temperature, water and 10% phosphoric acid aqueous solution were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. Dry with sodium sulfate, remove the solvent by distillation under reduced pressure, and subject the obtained residue to column chromatography purification (hexane: ethyl acetate), thereby obtaining N-(5-(tert-butyl)- 2-Chloro-4-methylphenyl)acetamide (954 mg). (Step 4) In addition to using N-(5-(tert-butyl)-2-chloro-4-methylphenyl)acetamide (954 mg) obtained in the above-mentioned Step 3, the method in Production Example 1 (Step 4) ), except for the N-(2-bromo-5-(tert-butyl)-4-chlorophenyl)acetamide used, the same method as in Production Example 1 (steps 4 and 5) was carried out, thereby 5-(tert-butyl)-2-chloro-4-methylbenzonitrile (517 mg) was obtained. (Step 5) To the N-methylpyrrolidone (4.00 mL) solution of 5-(tert-butyl)-2-chloro-4-methylbenzonitrile (517 mg) obtained in the above step 4, add anhydrous hydrazine (400 μL), and reacted at 130°C for 2 hours using a microwave reaction device, and continued to react at 140°C for 6 hours. Water was added to the reaction liquid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography purification (chloroform:ethanol) to obtain the title compound (88 mg).

Manufacturing example 7 5-(tert-butyl)-1H-indazole-3-amine 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (99.9 mg) obtained in Production Example 1 was dissolved in methanol (10 mL), and 7.5% palladium on carbon (19.6 mg) was added. A solution of hydrogen chloride in methanol (1 mL) was stirred vigorously under a hydrogen atmosphere at room temperature for 5 days. The insoluble matter was filtered off through celite, and the filtrate was concentrated to obtain the title compound (84 mg).

Manufacturing example 8 6-Chloro-5-(3,3,3-trifluoroprop-1-en-2-yl)-1H-indazol-3-amine (Step 1) Dissolve 5-bromo-6-chloro-1H-indazol-3-amine hydrochloride (800 mg) and 4-dimethylaminopyridine (18 mg) obtained in Production Example 2 (Step 3) To dichloromethane (10 mL), N,N-diisopropylamine (2 mL) and di-tert-butyl dicarbonate (1.2 g) were added. After stirring at room temperature overnight, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. To the obtained monoBoc body were added dichloromethane (10 mL), 4-dimethylaminopyridine (18 mg), N,N-diisopropylamine (2 mL) and di-tert-butyl dicarbonate (2.4 g ) and stir at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over ammonium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(bis(tert-butoxycarbonyl)amine (1.2 g)-5-bromo-6-chloro-indazole-1-carboxylate. (Step 2) To tert-butyl 3-(bis(tert-butoxycarbonyl)amino)-5-bromo-6-chloro-indazole-1-carboxylate obtained in step 1 above (250 mg) To a solution of 1,4-dioxane (7 mL), add 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2 -Dioxaborane (200 mg), 0.5 M aqueous potassium phosphate solution (2.7 mL) and 1,1'-bis(diphenylphosphino)ironium-palladium(II) dichloride-dichloromethane complex and stir at 100°C for 2 hours. The reaction liquid was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over ammonium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(bis(tert-butoxycarbonyl)amine yl)-6-chloro-5-(3,3,3-trifluoroprop-1-en-2-yl)-indazole-1-carboxylate (62 mg). (Step 3) To tert-butyl 3-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-(3,3,3-trifluoropropyl-1- obtained in step 2 above) To a solution of en-2-yl)-indazole-1-carboxylate (62 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining the title compound (14 mg).

Manufacturing example 9 6-Chloro-5-(1-(trifluoromethyl)cyclopropyl)-1H-indazole-3-amine (Step 1) To a solution of N-methyl-N-nitrosourea (265 mg) in diethyl ether (15 mL), an aqueous solution (4 mL) of potassium hydroxide (800 mg) was added under ice cooling, and stirred for 15 minutes ( Let be solution A). For tert-butyl 3-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-(3,3,3-trifluoropropyl-1- obtained in Production Example 8 (Step 2) A solution of en-2-yl)-indazole-1-carboxylate (73 mg) in diethyl ether (30 mL) was added dropwise to the solution A under ice-cooling for 30 minutes, and then stirred at room temperature overnight. After adding acetic acid, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography purification (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(bis(tert-butoxy (carbonyl)amino)-6-chloro-5-(5-(trifluoromethyl)-3,4-dihydropyrazol-5-yl)-indazole-1-carboxylate (64 mg). (Step 2) Use tert-butyl 3-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-(5-(trifluoromethyl)-3,4 obtained in the above step 1 A solution of -dihydropyrazol-5-yl)-indazole-1-carboxylate (64 mg) in xylene (3 mL) was stirred at 140° C. overnight, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography purification (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(bis(tert-butoxycarbonyl)amine)-6-chloro-5-( 1-(Trifluoromethyl)cyclopropyl)-indazole-1-carboxylate (52 mg). (Step 3) To tert-butyl 3-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-(1-(trifluoromethyl)cyclopropyl) obtained in step 2 above - A solution of indazole-1-carboxylate (52 mg) in dichloromethane (2 mL) was added with trifluoroacetic acid (1 mL) and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining the title compound (14 mg).

Manufacturing example 10 6-Chloro-5-isopropyl-1H-indazole-3-amine (Step 1) Acetic anhydride (1.54 mL) was added to a solution of 3-isopropylaniline (2.00 g) in ethyl acetate (20 mL), and the mixture was concentrated under reduced pressure after 20 minutes. To the residue were added 1,4-dioxane (20 mL), 1,3-bis(1-adamantyl)-1H-imidazolidinium tetrafluoroborate (61.7 mg), and D-(+)-10-camphor. Sulfonic acid (1.72g), N-chlorosuccinimide (1.97g), and stirred at room temperature for 13 hours. The reaction solution was concentrated, ethyl acetate and saturated sodium bicarbonate aqueous solution were added to the obtained residue, and the organic layer was separated. The organic layer was washed with saturated brine, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography and purification (hexane:ethyl acetate=88:12-0:100), thereby obtaining N-(4-chloro-3-isopropyl-phenyl)acetamide (2.52g) and N-(2-chloro-5-isopropylphenyl)acetamide (0.729g). (Step 2) Use N-(4-chloro-3-isopropylphenyl)acetamide (2.52g), N-bromosuccinimide (2.33g), and acetic acid (15mL) obtained in the above step 1. The solution was stirred at 60°C for 3 hours. The reaction liquid was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane:ethyl acetate=62:38), thereby obtaining N-(2-bromo-4-chloro-5- Isopropyl-phenyl)acetamide (2.82g). (Step 3) Instead of using N-(2-bromo-4-chloro-5-isopropyl-phenyl)acetamide (2.82 g) obtained in the above-mentioned Step 2, use it in Production Example 1 (Step 4). Except for N-(2-bromo-5-(tert-butyl)-4-chlorophenyl)acetamide, the same method as in Production Example 1 (steps 4 and 5) was carried out to obtain 2-bromo -4-Chloro-5-isopropyl-benzonitrile (1.82 g). (Step 4) In addition to using 2-bromo-4-chloro-5-isopropyl-benzonitrile (763 mg) obtained in the above-mentioned Step 3 instead of the 2-bromo-5-( used in Production Example 1 (Step 6) Except for tert-butyl)-4-chlorobenzonitrile, the same method as in Production Example 1 (steps 6 and 7) was carried out to obtain the title compound (333 mg).

Manufacturing example 11 Methyl 4-fluoro-1H-imidazole-5-carboxylate (Step 1) Methanesulfonic acid (90 mL) was added to a solution of 4-amino-1H-imidazole-5-carboxamide (52 g) in methanol (300 mL), and the mixture was stirred at 110° C. for 3 days. The solution was concentrated under reduced pressure, and a 5N sodium hydroxide aqueous solution was added, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine. After drying over sodium sulfate, the solvent was distilled off under reduced pressure to obtain crude methyl 4-amino-1H-imidazole-5-carboxylate (33 g). (Step 2) To a 42% tetrafluoroboric acid (40 mL) solution of methyl 4-amino-1H-imidazole-5-carboxylate (5.5 g) obtained in step 1 above, sodium nitrite ( 5.4 g) in water (3 mL) and stirred for 15 minutes. Move the reaction solution gently to the glass dish and irradiate it with 6W・302nm UV light from a distance of 3cm overnight. A 5N sodium hydroxide aqueous solution was added under ice cooling, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography purification (hexane: ethyl acetate) to obtain the title compound (1.1 g).

Manufacturing example 12 Methyl 4-chloro-1H-imidazole-5-carboxylate Concentrated hydrochloric acid (20 mL) was added to methyl 4-amino-1H-imidazole-5-carboxylate (4.5 g) obtained in Production Example 11 (step 1), and sodium nitrite (3.3 g) was added dropwise under ice cooling. aqueous solution (1.5 mL), stirred at the same temperature for 15 minutes. After the reaction solution was slowly moved to the glass dish, 302nm UV light was irradiated from a distance of 3cm overnight. Under ice-cooling, a 5N sodium hydroxide aqueous solution was added, and the precipitated solid was collected and heated to dryness overnight to obtain the title compound (2.6 g).

Manufacturing example 13 4-Chloro-1-methyl-1H-imidazole-5-carboxylic acid (Step 1) To a solution of methyl 4-chloro-1H-imidazole-5-carboxylate (600 mg) obtained in Production Example 12 in THF (7 mL), methanol (150 μL), triphenylphosphine (1.2 g) and DIAD (880 μL) and stirred at room temperature for 30 min. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl 4-chloro-1-methyl-1H-imidazole-5- Carboxylic acid ester (360 mg). (Step 2) To the ethanol (2 mL) solution of methyl 4-chloro-1-methyl-1H-imidazole-5-carboxylate (360 mg) obtained in the above step 1, add 5N aqueous sodium hydroxide solution (1 mL), and stir at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, 5N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (285 mg).

Manufacturing example 14 2-(ethoxycarbonyl)thiazole-4-carboxylic acid To a solution of ethyl thiooxamate (1.02 g) in THF (20 mL) was added 3-bromopyruvate (1.29 g) and stirred at 50° C. overnight. The reaction solution was cooled to room temperature, ethyl acetate (5 mL) was added, and the obtained solid was collected to obtain the title compound (911 mg).

Manufacturing example 15 3-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid Potassium carbonate (850 mg) and methyl iodide (380 μL) were added to a solution of diethyl 3,5-pyrazoledicarboxylate (637 mg) in acetone (10 mL), and the mixture was stirred at room temperature overnight. Water and 10% phosphoric acid aqueous solution were added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (10 mL) and 2N potassium hydroxide aqueous solution (1.65 mL) were added to the obtained residue, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction liquid, and ethanol was distilled off under reduced pressure. A 10% phosphoric acid aqueous solution was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was collected to obtain the title compound (520 mg).

Manufacturing example 16 2-(diethoxymethyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid (Step 1) 1-Methyl-4-trifluoromethylimidazole (334 mg) was dissolved in THF (4.0 mL) and cooled to -78°C. After slowly adding butyllithium (1.55 M hexane solution, 1.60 mL) to the reaction mixture, a solution of DMF (250 μL) in THF (1.0 mL) was added. After stirring at -78°C for 1 hour, the temperature was raised to 0°C and stirred for 30 minutes. Water was added to the obtained mixture, extracted with ethyl acetate, and washed with 20% saline water. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography and purification (hexane:ethyl acetate=90:10-50:50), thereby obtaining 1-methyl-4-trifluoromethylimidazole-2-carbaldehyde (354 mg) . (Step 2) Dissolve 1-methyl-4-trifluoromethylimidazole-2-carbaldehyde (350 mg) obtained in the above step 1 in ethanol (7.0 mL), and add concentrated sulfuric acid (0.1 mL). After stirring at room temperature for 6 hours, ethyl acetate was added, and the obtained mixture was poured into saturated baking soda water containing 2N aqueous sodium hydroxide solution (1.8 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to obtain 2-(diethoxymethyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (480 mg). (Step 3) Dissolve 2-(diethoxymethyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (45 mg) obtained in the above step 2 in acetonitrile (0.45 mL) , add N-bromosuccinimide (50 mg) and stir overnight. The reaction solution was concentrated, water was added, and the mixture was extracted with a hexane-ethyl acetate (3:1) mixed solvent. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography purification (hexane:ethyl acetate=80:20-20:80), thereby obtaining 5-bromo-2-(diethoxymethyl)-1-methyl -4-(Trifluoromethyl)-1H-imidazole (15 mg). (Step 4) After cooling THF (4.0 mL) to -78°C, butyllithium (1.55 M hexane solution, 0.8 mL) was added. 5-bromo-2-(diethoxymethyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (200 mg) obtained in the above step 3 was added dropwise to the obtained mixture over 5 minutes. THF (1.5 mL) solution. After the obtained mixture was stirred at -78°C for 5 minutes, dry ice was added. After the reaction mixture was warmed to room temperature, a saturated aqueous ammonium chloride solution containing 2N hydrochloric acid (0.63 mL) was added. The obtained mixture was extracted with ethyl acetate to obtain the title compound (220 mg).

Manufacturing example 17 1-isopropyl-4-(trifluoromethyl)-2-vinyl-1H-imidazole-5-carboxylic acid (Step 1) Ethyl 2-bromo-5-(trifluoromethyl)-1H-imidazole-4-carboxylate (107 mg), THF (2.0 mL), 2-propanol (0.04 mL), triphenyl To the mixture of phosphine (0.123g) was added DIAD (0.086mL). After stirring at room temperature for 50 minutes, the reaction solution was concentrated, and the obtained residue was subjected to column chromatography purification (hexane: ethyl acetate = 100:0-70:30), thereby obtaining 2-bromo-1 -Isopropyl-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid ethyl ester (89 mg). (Step 2) Use 2-bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid ethyl ester (413 mg) obtained in the above step 1, potassium ethylene trifluoroborate ( 0.185g), (1,1'-bis(diphenylphosphino)ironium)palladium(II) dichloride dichloromethane adduct (0.051g), 1,4-dioxane (4mL), and 2N aqueous sodium carbonate solution (1.6 mL) was stirred at 90°C for 7 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and 20% brine, and dried over sodium sulfate. After filtering the insoluble matter, the filtrate was concentrated, and the obtained residue was purified by column chromatography (hexane: ethyl acetate = 100:0-70:30), thereby obtaining it as a colorless oily substance 1-Isopropyl-4-(trifluoromethyl)-2-vinyl-1H-imidazole-5-carboxylic acid ethyl ester (252 mg). (Step 3) Dissolve 1-isopropyl-4-(trifluoromethyl)-2-vinyl-1H-imidazole-5-carboxylic acid ethyl ester (252 mg) obtained in the above step 2 in THF (3 mL) , add methanol (2.0 mL) and 1N sodium hydroxide aqueous solution (2 mL). After the obtained mixture was stirred at room temperature for 40 minutes, 5N hydrochloric acid (0.4 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and 20% saline, and then dried over sodium sulfate. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (224 mg).

Manufacturing example 18 4-Bromo-1-methyl-2-vinyl-1H-imidazole-5-carboxylic acid (Step 1) N-bromosuccinimide (8.5 g) was added to a solution of methyl 1H-imidazole-5-carboxylate (3 g) in acetonitrile (20 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl 2,4-dibromo-1H-imidazole-5-carboxylic acid. Ester (3.7g). (Step 2) To a THF (30 mL) solution of methyl 2,4-dibromo-1H-imidazole-5-carboxylate (2 g) obtained in the above step 1, add methanol (300 μL) and triphenylphosphine (2.2 g) and DIAD (1.6 mL) and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl 2,4-dibromo-1-methyl-1H-imidazole. -5-carboxylate (1.6g). (Step 3) A solution of methyl 2,4-dibromo-1-methyl-1H-imidazole-5-carboxylate (1.6 g) obtained in the above step 2 in 1,4-dioxane (20 mL) Quaternary triphenylphosphine palladium (0) (380 mg) and tributylvinyltin (1.9 mL) were added, and stirred at 110°C overnight. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl 4-bromo-1-methyl-2-vinyl-1H. - Imidazole-5-carboxylate (900 mg). (Step 4) Add 5N sodium hydroxide to a solution of methyl 4-bromo-1-methyl-2-vinyl-1H-imidazole-5-carboxylate (900 mg) obtained in step 3 above in ethanol (9 mL). aqueous solution (4.5 mL) and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, 5N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (840 mg).

Manufacturing example 19 4-cyano-1-methyl-1H-imidazole-5-carboxylic acid (Step 1) Concentrated sulfuric acid (0.88 mL) was slowly added to a solution of 4,5-dicyanimidazole (4.00 g) in ethanol (20 mL), and superheated reflux was performed for 4 days. Ethyl acetate and water were added to the reaction solution, and the layers were separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine. The mixture was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Chloroform was added to the obtained residue, and the obtained solid was collected. An approximately 2:3 mixture (4.14 g) of the starting material and 4-cyano-1H-imidazole-5-carboxylic acid ethyl ester was obtained. (Step 2) To a DMF (10 mL) solution of the mixture of ethyl 4-cyano-1H-imidazole-5-carboxylate (1.00 g) obtained in step 1 above, add potassium carbonate (1.26 g) and methyl iodide (565 μL ) and stir at room temperature for 2 hours. Diethyl ether and water were added to the reaction solution for liquid separation, and the organic layer was washed with water and saturated brine. After drying with sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining 4-cyano-1-methyl-1H- Approximately 3:2 mixture of imidazole-5-carboxylic acid ethyl ester and 1-methyl-1H-imidazole-4,5-dicarbonitrile (531 mg). (Step 3) To the 4-cyano-1-methyl-1H-imidazole-5-carboxylic acid ethyl ester mixture (531 mg) obtained in the above step 2, add water (2.00 mL) and benzyltrimethylammonium hydroxide. 40% aqueous solution of the substance (850 μL). After stirring at room temperature for 40 minutes, 10% phosphoric acid aqueous solution and ethyl acetate were added to the reaction solution, and the obtained solid was collected to obtain the title compound (252 mg).

Manufacturing example 20 1-Cyclopropyl-4-methyl-1H-imidazole-5-carboxylic acid The synthesis was carried out with reference to Eur.J.Org.Chem.2010, 4312-4320.

(Step 1) To a solution of methylhydrazinocarboxylate (501 mg) in THF (10 mL) was added ethyl 2-chloroacetyl acetate (919 mg), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, and the obtained residue was purified by column chromatography (hexane: ethyl acetate = 90:10-50:50), and the oil obtained was powdered using hexane and ethyl acetate. The reaction mixture was filtered to obtain ethyl (3E)-2-chloro-3-(methoxycarbonylhydrazinylidene)butyrate (980 mg). (Step 2) To a solution of ethyl (3E)-2-chlorotriformaldehyde-3-(methoxycarbonylhydrazinylidene)butyrate (350 mg) obtained in step 1 above in acetonitrile (4 mL), triethyl was added amine (205 μL) and stirred at room temperature for 45 min. Cyclopropylamine (89.0 mg) and parformaldehyde (92.9 mg) were further added, and the mixture was reacted at 150° C. for 20 minutes using a microwave reaction device. The reaction solution was concentrated, and the obtained residue was subjected to column chromatography purification (hexane: ethyl acetate = 35:65-10:90), thereby obtaining ethyl 1-cyclopropyl-4-methyl-1H -Imidazole-5-carboxylate (240 mg). (Step 3) Dissolve ethyl 1-cyclopropyl-4-methyl-1H-imidazole-5-carboxylate (328 mg) obtained in step 2 above in methanol (5 mL), and add 4N aqueous sodium hydroxide solution (633 μL) and stirred at 100°C for 2 hours. 6N hydrochloric acid (430 μL) was added to the reaction solution and dried to obtain the title compound.

Manufacturing example 21 1-(tert-butyl)-4-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained by performing the same method as in Production Example 20 (Step 2) except that tert-butylamine was used instead of cyclopropylamine used in Production Example 20 (Step 2).

Manufacturing example 22 2-(hydroxymethyl)-4-methyl-1-(2,2,2-trifluoroethyl)-1H-imidazole-5-carboxylic acid (Step 1) In addition to using 2,2,2-trifluoroethylamine instead of cyclopropylamine used in Production Example 20 (Step 2), (tert-butyldimethylsiloxy)acetaldehyde was used instead of trifluoroethylamine. polyoxymethylene, and the same method as in Production Example 20 (step 2) was carried out to obtain ethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-1 -(2,2,2-Trifluoroethyl)-1H-imidazole-5-carboxylate (260 mg). (Step 2) To the ethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-1-(2,2,2-tris A 4N sodium hydroxide aqueous solution (512 μL) was added to a solution of fluoroethyl)-1H-imidazole-5-carboxylate (260 mg) in ethanol (5 mL), and the mixture was stirred at 100° C. for 2 hours and 30 minutes. The reaction liquid was cooled to room temperature, 6N hydrochloric acid was added to the reaction liquid, and the reaction liquid was dried to obtain the title compound.

Manufacturing example 23 Methyl (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-1H-imidazole-5-carboxylate The same method as in Production Example 13 (Step 1) was carried out except that (S)-1-(tert-butoxycarbonyl)-3-pyrrolidinol was used instead of methanol used in Production Example 13 (Step 1). , thereby obtaining the title compound (10.61g, >99%ee).

Manufacturing example 24 Methyl (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-1H-imidazole-5-carboxylate The same method as in Production Example 13 (Step 1) was performed except that (R)-1-(tert-butoxycarbonyl)-3-pyrrolidinol was used instead of methanol used in Production Example 13 (Step 1). , thereby obtaining the title compound (659mg, >99%ee).

Manufacturing example 25 Methyl (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-2-formyl-1H-imidazole-5-carboxylate (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-1H-imidazole-5-carboxylate (3.29 g) obtained in Production Example 23 was added THF (70 mL), DMF (3.18 mL), and cooled in an ice-methanol bath. 2,2,6,6-Tetramethylpiperidinylmagnesium chloride and lithium chloride complex (1MTHF/toluene solution, 40 mL) were added, and stirred for 30 minutes. Water and 10% phosphoric acid aqueous solution were added to the reaction liquid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate), and after concentration, hexane was added and the precipitated solid was collected to obtain the title compound (2.29 g).

Manufacturing example 26 Methyl 2-formyl-4-iodo-1-methyl-1H-imidazole-5-carboxylate (Step 1) Dissolve 1-methyl-1H-imidazole-5-carboxylic acid methyl ester (0.51g) in acetonitrile (25mL), add N-iodosuccinimide (1.8g), and heat at 85°C Stir for 22 hours. N-iodosuccinimide (0.91g) was added, and the obtained mixture was heated and refluxed for 24 hours. Furthermore, N-iodosuccinimide (1.8 g) was added, and after heating and refluxing for 6 days, ethyl acetate was added at room temperature. The obtained mixture was washed with water, saturated sodium sulfite aqueous solution, and 20% brine, and the organic layer was dried over sodium sulfate. Insoluble matter was filtered out, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography and purification (hexane:ethyl acetate=90:10-70:30), thereby obtaining 2,5-diiodo-3-methylimidazole-4-carboxylic acid methyl ester. (229mg). (Step 2) Use 2,5-diiodo-3-methylimidazole-4-carboxylic acid methyl ester (102 mg) obtained in the above step 1, potassium ethylene trifluoroborate (0.035g), (1,1'- Bis(diphenylphosphino)ironium)palladium(II) dichloride dichloromethane adduct (0.013g), 1,4-dioxane (2mL), and 2N aqueous sodium carbonate solution (0.3mL) The mixture was stirred at 90°C for 2 hours. Potassium ethylene trifluoroborate (0.014g) and 2N aqueous sodium carbonate solution (0.1 mL) were further added, and the mixture was stirred at 90° C. for 1 hour, and then water was added at room temperature. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated. The obtained residue was subjected to column chromatography and purification (hexane:ethyl acetate=90:10-30:70), thereby obtaining 5-iodo-3-methyl-2-vinylimidazole-4-carboxylic acid Methyl ester (43 mg). (Step 3) Use 5-iodo-3-methyl-2-vinylimidazole-4-carboxylic acid methyl ester (62 mg) obtained in the above step 2, 1,4-dioxane (1 mL), and water (0.2 mL), 2,6-lutidine (0.045 mL), aqueous osmium tetroxide solution (0.15 M, 0.031 mL), and sodium periodate (0.16 g) were stirred at room temperature for 17 hours. The reaction mixture was extracted with ethyl acetate, washed with water and 20% brine, and dried over sodium sulfate. Filter out the insoluble matter and concentrate the filtrate under reduced pressure. The obtained residue was subjected to column chromatography purification (hexane:ethyl acetate=90:10-40:60) to obtain the title compound (47 mg).

Manufacturing example 27 1-(3-Aminoazetidin-1-yl)prop-2-en-1-one hydrochloride (Step 1) 3-Boc-aminoazetidine hydrochloride (10 g) was suspended in acetonitrile (120 mL), and 1 M aqueous sodium bicarbonate solution (96 mL) was added at room temperature. Under ice-cooling, acrylonitrile chloride (4.7 mL) and acetonitrile (10 mL) were added, and the mixture was stirred for 30 minutes under ice-cooling. Add water and ethyl acetate and filter to remove insoluble matter. After the aqueous layer was separated and extracted with ethyl acetate, the organic layer was dried over sodium sulfate and the solvent was distilled off. The residue was suspended in a mixed solution of tert-butyl methyl ether (20 mL) and hexane (20 mL), and stirred at room temperature for 1 hour. The precipitate was filtered, washed with hexane (80 mL), and dried to obtain tert-butyl N-(1-prop-2-enyl azedine-3-yl)carbamate ( 10.2g). (Step 2) Suspend tert-butyl N-(1-prop-2-enyl azetidin-3-yl)carbamate (10.2 g) in acetonitrile (10 mL) and 5N hydrochloric acid (25 mL) , stir at room temperature for 3 hours. After concentrating the solution, a mixed solution (55 mL) of acetone:methanol=10:1 was added, and the mixture was stirred at room temperature for 1 hour. The precipitate was filtered, washed with a mixed solution (50 mL) of acetone:methanol=10:1, and dried to obtain the title compound (5.7 g).

Manufacturing example 28 1-(4-Amino-3,3-difluoropyrrolidin-1-yl)prop-2-en-1-one trifluoroacetate (Step 1) tert-butyl N-(4,4-difluoropyrrolidin-3-yl)carbamate (100 mg) was suspended in THF (2 mL), and N,N- was added at room temperature. Diisopropylethylamine (0.16 mL), followed by diacrylic anhydride (0.052 mL) was added under ice-cooling. After stirring under ice-cooling for 45 minutes, ethyl acetate, water and a saturated sodium bicarbonate aqueous solution were added, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was subjected to column chromatography purification (chloroform:methanol), thereby obtaining tert-butyl N-(4,4-difluoro-1-prop-2-enyl-pyrrolidin-3-yl ) carbamate (121 mg). (Step 2) Dissolve tert-butyl N-(4,4-difluoro-1-prop-2-enyl-pyrrolidin-3-yl)carbamate (26 mg) in chloroform (1 mL) , add trifluoroacetic acid (0.5 mL) at room temperature, and stir at room temperature for 1 hour. After the solution was concentrated, chloroform was added and the solution was concentrated again, and then THF was added and the solvent was distilled off to obtain the title compound (26.8 mg).

Manufacturing example 29 (R)-1-(7-Amino-5-azaspiro[2.4]heptan-5-yl)prop-2-en-1-one trifluoroacetate (Step 1) Dissolve tert-butyl N-((7R)-5-azaspiro[2.4]heptan-7-yl)carbamate (100 mg) in THF (1 mL) and incubate at room temperature N,N-diisopropylethylamine (0.16 mL) was added under ice-cooling, and then diacrylic anhydride (0.054 mL) was added under ice-cooling. After stirring under ice-cooling for 10 minutes, ethyl acetate and water were added, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to column chromatography and purification (chloroform:methanol), thereby obtaining tert-butyl N-((7R)-5-prop-2-enyl-5-azaspiro[2.4]hepta Alk-7-yl)carbamate (108 mg). (Step 2) Dissolve tert-butyl N-[(7R)-5-prop-2-enyl-5-azaspiro[2.4]heptan-7-yl]carbamate (19 mg) in To chloroform (1 mL), trifluoroacetic acid (0.5 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour and 20 minutes. After the solution was concentrated, chloroform was added for re-concentration, and then THF was added and the solvent was distilled off to obtain the title compound (19 mg).

Manufacturing example 30 1-((3R,4R)-3-amino-4-methylpyrrolidin-1-yl)prop-2-en-1-one trifluoroacetate (Step 1) Dissolve tert-butyl N-((3R,4R)-4-methylpyrrolidin-3-yl)carbamate (100 mg) in THF (1 mL), and add N at room temperature , N-diisopropylethylamine (0.17mL), then diacrylic anhydride (0.058mL) was added under ice cooling. After stirring under ice-cooling for 10 minutes, ethyl acetate, water and a saturated sodium bicarbonate aqueous solution were added, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to column chromatography purification (chloroform:methanol) to obtain tert-butyl N-((3R,4R)-4-methyl-1-prop-2-enyl-pyrrolidine -3-yl)carbamate (111 mg). (Step 2) Dissolve tert-butyl N-[(3R,4R)-4-methyl-1-prop-2-enyl-pyrrolidin-3-yl]carbamate (35 mg) in chloroform (1 mL), trifluoroacetic acid (0.5 mL) was added at room temperature, and stirred at room temperature for 45 minutes. After the solution was concentrated, chloroform was added and the solution was concentrated again, and then THF was added and the solvent was distilled off to obtain the title compound (35 mg).

Manufacturing example 31 tert-Butyl (3R,4R)-3-amino-4-(cyanomethyl)pyrrolidine-1-carboxylate (Step 1) Dissolve tert-butyl (3S,4S)-3-hydroxy-4-(hydroxymethyl)pyrrolidine-1-carboxylate (700 mg) in dichloromethane (7 mL) at room temperature. N,N-diisopropylethylamine (1.12 mL) was added under ice-cooling, and then methane sulfonyl chloride (0.25 mL) was added under ice-cooling. After stirring under ice-cooling for 2 hours, chloroform and water were added, the aqueous layer was separated, and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to column chromatography purification (chloroform:methanol) to obtain tert-butyl(3S,4S)-3-hydroxy-4-(methylsulfonyloxymethyl)pyrrolidine- 1-carboxylate (776 mg). (Step 2) Dissolve tert-butyl(3S,4S)-3-hydroxy-4-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate (400 mg) in DMSO (4 mL) , after adding sodium cyanide (334 mg) at room temperature, the mixture was stirred at room temperature for 1 hour and 30 minutes. DMSO (4 mL) was additionally added, and the mixture was stirred at room temperature for 1 hour, and then stirred at 50° C. overnight. To the reaction solution, ethyl acetate, water and a saturated sodium bicarbonate aqueous solution were added at room temperature, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The obtained residue is subjected to column chromatography and purification (chloroform:methanol), thereby obtaining tert-butyl (3R,4S)-3-(cyanomethyl)-4-hydroxy-pyrrolidine-1-carboxylic acid Ester (386mg, 74wt%). (Step 3) Dissolve tert-butyl (3R,4S)-3-(cyanomethyl)-4-hydroxy-pyrrolidine-1-carboxylate (200 mg) in dichloromethane (2 mL). Triethylamine (0.14 mL) was added at room temperature, and then methane sulfonyl chloride (0.056 mL) was added under ice cooling. After stirring under ice-cooling for 20 minutes, chloroform and water were added, the aqueous layer was separated, and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off to obtain tert-butyl(3R,4S)-3-(cyanomethyl)-4-methylsulfonyloxy pyrrolidine-1-carboxylate (203 mg). (Step 4) Dissolve tert-butyl(3R,4S)-3-(cyanomethyl)-4-methylsulfonyloxy-pyrrolidine-1-carboxylate (199 mg) in acetonitrile (2 mL ), after adding tetrakis-N-butylammonium azide (279 mg) at room temperature, the mixture was stirred at room temperature for 10 minutes and at 50° C. for 1 hour. The temperature was raised to 80°C and stirred for 3 hours, then stirred at 85°C for 2 hours and 30 minutes, and then at 90°C for 1 hour and 30 minutes. After the reaction solution was concentrated, the obtained residue was purified by column chromatography (ethyl acetate:hexane), thereby obtaining tert-butyl(3R,4R)-3-azido-4-(cyanomethyl pyrrolidine-1-carboxylate (137 mg). (Step 5) Dissolve tert-butyl (3R, 4R)-3-azido-4-(cyanomethyl)pyrrolidine-1-carboxylate (135 mg) in methanol (1 mL) to prepare nitrogen After ambient gas, 10% palladium on carbon (23 mg) was added at room temperature and stirred at room temperature for 2 hours under hydrogen ambient gas. The reaction solution was filtered through celite and washed with methanol, and then the solvent was distilled off to obtain the title compound (116 mg).

Manufacturing example 32 tert-Butyl (3R,4R)-3-amino-4-(fluoromethyl)pyrrolidine-1-carboxylate (Step 1) Using tert-butyl(3S,4S)-3-hydroxy-4-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate obtained in Production Example 31 (Step 1) (180 mg) was dissolved in THF (2 mL) and 1 M tetrabutylammonium fluoride in THF (1.83 mL) was added at room temperature. After stirring at room temperature for 40 minutes and at 50°C for 30 minutes, the mixture was stirred at 65°C overnight. 1M tetrabutylammonium fluoride in THF solution (1.83 mL) was additionally added at room temperature, and stirred at 65°C for 3 hours. Ethyl acetate and water were added to the reaction solution at room temperature, and the organic layer was added with Wash with water and saturated salt water. After drying with sodium sulfate, the solvent was distilled off, and the obtained residue was purified by column chromatography (chloroform:methanol), thereby obtaining tert-butyl (3R,4S)-3-(fluoromethyl)-4- Hydroxy-pyrrolidine-1-carboxylate (62 mg). (Step 2) Dissolve tert-butyl (3R,4S)-3-(fluoromethyl)-4-hydroxy-pyrrolidine-1-carboxylate (62 mg) in dichloromethane (1.5 mL). Triethylamine (0.059 mL) was added at room temperature, and then methane sulfonyl chloride (0.024 mL) was added under ice cooling. After stirring under ice-cooling for 20 minutes, ethyl acetate and water were added, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and the solvent was distilled off to obtain tert-butyl(3R,4S)-3-(fluoromethyl)-4- Methylsulfonyloxy-pyrrolidine-1-carboxylate (78 mg). (Step 3) Dissolve tert-butyl(3R,4S)-3-(fluoromethyl)-4-methylsulfonyloxy-pyrrolidine-1-carboxylate (78 mg) in acetonitrile (1.5 mL ), after adding tetrakis-N-butylammonium azide (112 mg) at room temperature, the mixture was stirred at 80° C. for 3 hours. After additionally adding a solution of tetrakis-N-butylammonium azide (75 mg) in acetonitrile (0.5 mL) at room temperature, the mixture was stirred at 80°C for 1 hour and then at 90°C for 2 hours. Ethyl acetate, water, and saturated brine were added to the reaction solution at room temperature, and the organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to column chromatography purification (ethyl acetate:hexane) to obtain tert-butyl(3R,4R)-3-azido-4-(fluoromethyl)pyrrolidine-1- Carboxylic acid ester (58 mg). (Step 4) Dissolve tert-butyl (3R, 4R)-3-azido-4-(fluoromethyl)pyrrolidine-1-carboxylate (58 mg) in methanol (1 mL) and make nitrogen After ambient gas, 10% palladium on carbon (13 mg) was added at room temperature, and stirred under hydrogen ambient gas at room temperature for 1 hour and 30 minutes. The reaction solution was filtered through diatomaceous earth and washed with chloroform and methanol, and then the solvent was distilled off. The obtained residue was subjected to alkaline silica gel column chromatography purification (ethyl acetate:hexane) to obtain the title compound (45 mg).

Manufacturing example 33 tert-Butyl (3R,4R)-3-amino-4-(methoxymethyl)pyrrolidine-1-carboxylate (Step 1) Using tert-butyl(3S,4S)-3-hydroxy-4-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate obtained in Production Example 31 (Step 1) (200 mg) was dissolved in methanol (2 mL), and 25% sodium methoxide in methanol (0.16 mL) was added at room temperature. After stirring at room temperature for 40 minutes and at 50°C for 1 hour and 40 minutes, an additional 25% methanol solution of sodium methoxide (0.16 mL) was added at 50°C, and stirred at 50°C for 1 hour and 40 minutes. Then, stir at 65°C for 2 days. Furthermore, a 25% methanol solution of sodium methoxide (0.16 mL) was additionally added at room temperature, and the mixture was stirred at 65° C. for 8 hours. Ethyl acetate and water were added to the reaction solution at room temperature, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine. After drying with sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane), thereby obtaining tert-butyl (3S, 4S)-3. -Hydroxy-4-(methoxymethyl)pyrrolidine-1-carboxylate (81 mg). (Step 2) Dissolve tert-butyl(3S,4S)-3-hydroxy-4-(methoxymethyl)pyrrolidine-1-carboxylate (81 mg) in dichloromethane (1.5 mL), Triethylamine (0.073 mL) was added at room temperature, and then methane sulfonyl chloride (0.030 mL) was added under ice cooling. After stirring under ice-cooling for 20 minutes, ethyl acetate and water were added, the aqueous layer was separated, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off to obtain tert-butyl(3S,4S)-3-(methoxymethyl)-4-methylsulfonate. Oxy-pyrrolidine-1-carboxylate (107 mg). (Step 3) Dissolve tert-butyl(3S,4S)-3-(methoxymethyl)-4-methylsulfonyloxy-pyrrolidine-1-carboxylate (107 mg) in DMF ( 1.5 mL), and sodium azide (42 mg) was added at room temperature, followed by stirring at 80° C. for 6 hours and 30 minutes, and at room temperature overnight. After the reaction solution was stirred again at 80° C. for 5 hours and 20 minutes, sodium azide (44 mg) was additionally added at room temperature, and the mixture was stirred at 80° C. for 10 hours and at room temperature overnight. Ethyl acetate and water were added to the reaction solution at room temperature, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was purified by column chromatography (ethyl acetate:hexane), thereby obtaining tert-butyl(3R,4R)-3-azido-4-(methoxymethyl)pyrrolidine- 1-Carboxylic acid ester (83 mg). (Step 4) Dissolve tert-butyl (3R, 4R)-3-azido-4-(methoxymethyl)pyrrolidine-1-carboxylate (83 mg) in methanol (1 mL) to prepare After nitrogen atmosphere, 10% palladium on carbon (13 mg) was added at room temperature, and stirred for 2 hours under hydrogen atmosphere at room temperature. The reaction solution was filtered through diatomaceous earth and washed with chloroform and methanol, and then the solution was distilled off. The obtained residue was purified by alkaline silica gel column chromatography (ethyl acetate:hexane) to obtain the title compound (72 mg).

Manufacturing example 34 tert-Butyl (3R,4R)-3-amino-4-((dimethylamino)methyl)pyrrolidine-1-carboxylate (Step 1) Dissolve tert-butyl (3S,4S)-3-hydroxy-4-(hydroxymethyl)pyrrolidine-1-carboxylate (300 mg) in DMF (3 mL) and add at room temperature A solution of imidazole (122 mg) and tert-butyldimethylsilyl chloride (208 mg) in DMF (0.5 mL) was stirred at room temperature for 30 minutes. Ethyl acetate and water were added to the reaction solution, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer was washed with saturated salt, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to column chromatography purification (hexane: ethyl acetate, chloroform: methanol), thereby obtaining tert-butyl(3S,4S)-3-((tert-butyl(dimethyl)) Silyl)oxymethyl)-4-hydroxy-pyrrolidine-1-carboxylate (307 mg). (Step 2) tert-butyl(3S,4S)-3-((tert-butyl(dimethyl)silyl)oxymethyl)-4-hydroxy-pyrrolidine-1-carboxylate ( 295 mg) was dissolved in dichloromethane (3 mL), triethylamine (0.19 mL) was added at room temperature, and then methane sulfonyl chloride (0.078 mL) was added under ice cooling. After stirring under ice-cooling for 10 minutes, ethyl acetate and water were added, and the organic layer was washed with saturated brine. Dry with sodium sulfate and distill off the solvent to obtain tert-butyl(3S,4S)-3-((tert-butyl(dimethyl)silyl)oxymethyl)-4-methylsulfonate Cyloxy-pyrrolidine-1-carboxylate (368 mg). (Step 3) tert-butyl(3S,4S)-3-((tert-butyl(dimethyl)silyl)oxymethyl)-4-methylsulfonyloxy-pyrrolidine- 1-carboxylic acid ester (365 mg) was dissolved in DMF (3 mL), and sodium azide (95 mg) was added at room temperature, followed by stirring at 80° C. overnight. Sodium azide (96 mg) was additionally added at room temperature, and the mixture was stirred at 80° C. overnight. Ethyl acetate and water were added to the reaction solution at room temperature, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to obtain tert-butyl(3R,4R)-3-azide-4-((tert-butyl(dimethyl) Silyl)oxymethyl)pyrrolidine-1-carboxylate (410 mg). (Step 4) tert-butyl(3R,4R)-3-azido-4-((tert-butyl(dimethyl)silyl)oxymethyl)pyrrolidine-1-carboxylate ( 317 mg) was dissolved in THF (2 mL), and a 1 M THF solution of tetrabutylammonium fluoride (0.98 mL) was added at room temperature, followed by stirring at room temperature for 1 hour. Ethyl acetate, water, and saturated brine were added to the reaction solution at room temperature, and the aqueous layer was separated and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane) to obtain tert -Butyl(3R,4R)-3-azido-4-(hydroxymethyl)pyrrolidine-1-carboxylate (221 mg). (Step 5) Dissolve tert-butyl (3R,4R)-3-azido-4-(hydroxymethyl)pyrrolidine-1-carboxylate (100 mg) in dichloromethane (2 mL). Triethylamine (0.086 mL) was added at warm temperature, and then methane sulfonyl chloride (0.035 mL) was added under ice cooling. After stirring under ice-cooling for 15 minutes, ethyl acetate and water were added, and the organic layer was washed with saturated brine. Drying with sodium sulfate and distilling off the solvent, thereby obtaining tert-butyl (3R, 4R)-3-azide-4-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate ( 133mg). (Step 6) Dissolve tert-butyl(3R,4R)-3-azido-4-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate (63 mg) in DMF (1 mL) , sodium iodide (8 mg) and 2M dimethylamine in THF solution (1.03 mL) were added at room temperature. After using a microwave reaction device to react at 80°C for 12 hours, DMF (1 mL) and a 2M dimethylamine THF solution (0.52 mL) were added, and using a microwave reaction device to react at 80°C for 6 hours. . Further, sodium iodide (8 mg) and 2M dimethylamine in THF solution (1.03 mL) were added, and the mixture was reacted at 80° C. for 12 hours using a microwave reaction device, and then stirred at 80° C. for 9 hours. Ethyl acetate and water were added to the reaction solution at room temperature, and the organic layer was washed with saturated brine. After drying with sodium sulfate, the solvent was distilled off, and the obtained residue was purified by alkaline silica gel column chromatography (ethyl acetate:hexane), thereby obtaining tert-butyl (3R, 4R)-3-azide. Nitrogen-4-((dimethylamino)methyl)pyrrolidine-1-carboxylate (41 mg). (Step 7) Dissolve tert-butyl(3R,4R)-3-azido-4-((dimethylamino)methyl)pyrrolidine-1-carboxylate (40 mg) in methanol (1 mL) , after making a nitrogen atmosphere, add 10% palladium on carbon (12 mg) at room temperature, and stir for 2 hours under a hydrogen atmosphere at room temperature. The reaction solution was filtered through celite and washed with methanol and chloroform, and then the solvent was distilled off. The obtained residue was subjected to alkaline silica gel column chromatography and purification (ethyl acetate:hexane) to obtain the title compound (11 mg).

Manufacturing example 35 N-(1-propenyl azedine-3-yl)-2-formyl-1-methyl-1H-imidazole-5-formamide (Step 1) A mixture of methyl 1-methyl-1H-imidazole-5-carboxylate (0.5g) and formaldehyde aqueous solution (37%, 2mL) was stirred for 2 hours at 140°C under microwave irradiation. . 0.2 g of common salt was added to the obtained mixture, and the mixture was extracted with ethyl acetate. After concentrating the organic layer, the obtained residue was subjected to column chromatography and purification (ethyl acetate:methanol=99:1-90:10), thereby obtaining methyl 2-(hydroxymethyl)-3-methylimidazole. -4-carboxylate (0.38g). (Step 2) Dissolve methyl 2-(hydroxymethyl)-3-methylimidazole-4-carboxylate (0.38g) obtained in step 1 above in chloroform (8mL), and add manganese dioxide (1.0 g), and heated to reflux for 2 hours. After cooling to room temperature, the insoluble matter was filtered through diatomaceous earth, and the filtrate was concentrated. The obtained residue was subjected to column chromatography purification (hexane:ethyl acetate=90:10-50:50), thereby obtaining methyl 2-formyl-3-methylimidazole-4-carboxylate. (0.27g). (Step 3) Dissolve the methyl 2-formyl-3-methylimidazole-4-carboxylate (0.32g) obtained in the above step 2 in THF (1.5mL), add methanol (1.5mL), 2N aqueous sodium hydroxide solution (2.0 mL). The reaction solution was stirred at room temperature overnight and then concentrated to obtain a crude form of sodium 2-formyl-3-methylimidazole-4-carboxylate (0.29 g). (Step 4) Dissolve the crude form of sodium 2-formyl-3-methylimidazole-4-carboxylate (0.29 g) obtained in the above Step 3 in DMF (2.0 mL), and add to Production Example 27 Obtained 1-(3-aminoazetidin-1-yl)prop-2-en-1-one hydrochloride (0.37g), diisopropylethylamine (0.97mL), HATU (0.87g ). After the reaction solution was stirred at room temperature for 1 hour, water was added, and the mixture was extracted with a mixed solvent of chloroform:methanol (9:1). The organic layer was concentrated, and the obtained residue was subjected to column chromatography and purification (chloroform:methanol=96:4-90:10) to obtain a crude purified product. The crude purified product was suspended and washed with ethyl acetate to obtain the title compound (0.25 g).

Manufacturing example 36 tert-Butyl 3-(2-formyl-1,4-dimethyl-1H-imidazole-5-formamide)azetidine-1-carboxylate (Step 1) Add N to a solution of 1,4-dimethyl-1H-imidazole-5-carboxylic acid (1.00g) and 1-Boc-3-aminoazetidine (1.34mL) in DMF (14mL). N-diisopropylethylamine (4.00 mL), HATU (3.53 g), and stirred for 100 minutes. Ethyl acetate, water, and 10% phosphoric acid aqueous solution were added to the reaction solution for liquid separation, and the organic layer was washed with water and saturated brine. The mixture was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate). After concentration, diisopropyl ether was added, and the solid obtained was collected to obtain tert-butyl 3-(1,4-dimethyl-1H-imidazole-5-carboxamide) azetidine-1-carboxylate. (1.97g). (Step 2) Add THF to tert-butyl 3-(1,4-dimethyl-1H-imidazole-5-carboxamide) azetidine-1-carboxylate (500 mg) obtained in the above step 1 (15.0 mL), 2,2,6,6-tetramethylpiperidine (1.44 mL), and cooled with a dry ice acetone bath. Butyllithium (2.6M hexane solution, 4.00 mL) was added in 15 minutes. After stirring for 1 hour while cooling in a dry ice acetone bath, DMF (1.32 mL) was added, and the mixture was further stirred for 30 minutes. Add saturated aqueous ammonium chloride solution and warm to room temperature. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining the title compound (294 mg).

Manufacturing example 37 tert-butyl 3-(2-formyl-1-isopropyl-4-methyl-1H-imidazole-5-formamide)azetidine-1-carboxylate (Step 1) To a suspension of ethyl 4-methylimidazole-5-carboxylate (506 mg) in THF (10 mL), triphenylphosphine (1.02 g), 2-propanol (237 mg), and DIAD (772 μL ) and stir at room temperature for 30 minutes. The solution was concentrated under reduced pressure, and the obtained residue was subjected to column chromatography purification (hexane:ethyl acetate=33:67-10:90), thereby obtaining ethyl 1-isopropyl-4- Methyl-1H-imidazole-5-carboxylate (517 mg). (Step 2) To the ethanol (5 mL) solution of ethyl 1-isopropyl-4-methyl-1H-imidazole-5-carboxylate (517 mg) obtained in step 1 above, add 4N aqueous sodium hydroxide solution (988 μL ) and stir at 85°C for 1 hour. 6N hydrochloric acid (660 μL) was added to the reaction solution and dried. Add dichloromethane (5.0 mL), 1-hydroxybenzotriazole monohydrate (408 mg), 1-Boc-3-aminoazetidine (452 mg), diisopropylethylamine (1.34 mL), WSC hydrochloride (768 mg). Stir at room temperature for 3 days. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine. Dry with sodium sulfate, remove the solvent by distillation under reduced pressure, and subject the obtained residue to column chromatography purification (chloroform: methanol = 100:0-25:1), thereby obtaining tert-butyl 3-( 1-Isopropyl-4-methyl-1H-imidazole-5-methamide)azetidine-1-carboxylate (673 mg). (Step 3) tert-butyl 3-(1-isopropyl-4-methyl-1H-imidazole-5-carboxamide) azetidine-1-carboxylate obtained in the above step 2 (673 mg ) in THF (15 mL) was cooled in a dry ice ethanol bath, and butyllithium (2.76 M hexane solution, 4.5 mL) was added over 15 minutes. The mixture was stirred for 2 hours while cooling in a dry ice ethanol bath, DMF (1.1 mL) was added, and the mixture was further stirred for 5 minutes. A saturated aqueous ammonium chloride solution was added and the temperature was raised to room temperature. Extraction was performed with ethyl acetate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography purification (hexane:ethyl acetate=20:80-0:100-ethyl acetate:methanol=90/10) to obtain the title compound (465 mg).

Manufacturing example 38 tert-butyl 3-(4-chloro-2-formyl-1-isopropyl-1H-imidazole-5-formamide)azetidine-1-carboxylate (Step 1) To a THF (30 mL) solution of methyl 4-chloro-1H-imidazole-5-carboxylate (1.6 g) obtained in Production Example 12, 2-propanol (800 μL), triphenylphosphine ( 3.1g), and DIAD (2.4mL), and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl 4-chloro-1-isopropyl-1H-imidazole-5. - Carboxylic acid ester (1.9g). (Step 2) To the ethanol (9 mL) solution of methyl 4-chloro-1-isopropyl-1H-imidazole-5-carboxylate (1.9 g) obtained in the above step 1, add 5N aqueous sodium hydroxide solution (9 mL) ) and stir at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, 5N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain crude 4-chloro-1-isopropyl-1H-imidazole-5-carboxylic acid (1.8 g). (Step 3) To a solution of 4-chloro-1-isopropyl-1H-imidazole-5-carboxylic acid (1.8 g) obtained in step 2 above in DMF (12 mL), 1-Boc-3-aminoazedine was added 1.4 g), N,N-diisopropylethylamine (2.4 mL), and HATU (3.0 g), and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform:ethanol), thereby obtaining tert-butyl 3-(4-chloro-1-isopropyl-1H-imidazole) -5-Formamide)azetidine-1-carboxylate (1.8g). (Step 4) To tert-butyl 3-(4-chloro-1-isopropyl-1H-imidazole-5-methamide)azetidine-1-carboxylate (510 mg) obtained in the above step 3 To a solution of THF (13 mL), under nitrogen atmosphere, add 2,2,6,6-tetramethylpiperidine (1.03 mL) and cool to -78°C. Butyllithium (1.55 M hexane solution, 3.45 mL) was added dropwise to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. DMF was added and stirred for a further 1 hour at -78°C. Water and 10% phosphoric acid aqueous solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane:ethyl acetate=100:0-0:100), thereby obtaining the title compound (240 mg).

Manufacturing example 39 tert-butyl 3-(2-formyl-1-methyl-4-phenyl-1H-imidazole-5-formamide)azetidine-1-carboxylate (Step 1) To a solution of 4-bromo-1-methyl-2-vinyl-1H-imidazole-5-carboxylic acid (840 mg) obtained in Production Example 18 in dichloromethane (9 mL), 1-Boc-3 was added -Aminoazetidine (760mg), N,N-diisopropylethylamine (1.25mL), WSC hydrochloride (1.06g), 1-hydroxybenzotriazole (745mg), at room temperature Stir for 30 minutes. An aqueous solution of sodium bicarbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(4-bromo-1-methyl-2) -Vinyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (1.38 g). (Step 2) To tert-butyl 3-(4-bromo-1-methyl-2-vinyl-1H-imidazole-5-methamide)azetidine-1-carboxylic acid obtained in the above step 1 To a solution of ester (1.38g) in 1,4-dioxane (40mL), add water (6.45mL), sodium periodate (3.06g), 2,6-lutidine (830μL) and 0.15M aqueous osmium tetroxide solution (480 μL) and stir at room temperature overnight. After adding water and extracting with ethyl acetate, the organic layer was washed with an aqueous sodium thiosulfate solution and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(4-bromo-2-formyl- 1-Methyl-1H-imidazole-5-methamide)azetidine-1-carboxylate (760 mg). (Step 3) To tert-butyl 3-(4-bromo-2-formyl-1-methyl-1H-imidazole-5-formamide)azetidine-1-carboxylic acid obtained in the above step 2 A solution of acid ester (110 mg) in 1,4-dioxane (3 mL) was mixed with phenylboronic acid (35 mg), 2M aqueous sodium carbonate solution (425 μL), and 1,1'-bis(diphenylphosphino)ironoxine -Palladium (II) dichloride-dichloromethane complex (23 mg) and stirred for 3 hours at 90°C under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining the title compound (84 mg).

Manufacturing example 40 tert-butyl 3-(4-ethyl-2-formyl-1-methyl-1H-imidazole-5-formamide)azetidine-1-carboxylate (Step 1) To a solution of methyl hydrazinocarboxylate (482 mg) in THF (10 mL) was added methyl 2-chloro-3-oxopentanoate (840 mg), and the mixture was stirred at room temperature for 19 hours. The reaction solution was concentrated, and the obtained residue was subjected to column chromatography and purification (hexane: ethyl acetate = 90:10-50:50), thereby obtaining methyl (3E)-2-chloro-3-(methane) Oxycarbonylhydrazinylidene)valerate (1.13g). (Step 2) To a solution of methyl(3E)-2-chloro-3-(methoxycarbonylhydrazinylidene)valeric acid (496 mg) obtained in step 1 above in acetonitrile (10 mL), triethylamine (291 μL ) and stir at room temperature for 20. Further, a THF solution of methylamine (7%, 1.3 mL) and (tert-butyldimethylsiloxane)acetaldehyde (799 μL) were added, and the mixture was reacted at 150° C. for 20 minutes in a microwave reaction device. The reaction solution was concentrated, and the obtained residue was subjected to column chromatography and purification (hexane:ethyl acetate=80:20-50:50), thereby obtaining methyl 2-((tert-butyldimethylsilica) (yl)oxymethyl)-4-ethyl-1-methyl-1H-imidazole-5-carboxylate (587 mg). (Step 3) To the methyl 2-((tert-butyldimethylsilyl)oxymethyl)-4-ethyl-1-methyl-1H-imidazole-5-carboxylic acid obtained in the above step 2 A 4N aqueous sodium hydroxide solution (1.17 mL) was added to a solution of the acid ester (587 mg) in methanol (5 mL), and stirred at 100° C. for 1 hour. 6N hydrochloric acid (790 μL) was added to the reaction solution and dried to obtain 5-ethyl-2-(hydroxymethyl)-3-methyl-imidazole-4-carboxylic acid. Suspend it in DMF (2 mL), and add 1-hydroxybenzotriazole monohydrate (288 mg), 1-Boc-3-aminoazetidine (320 mg), and diisopropylethylamine (958 μL). , WSC hydrochloride (541 mg), and stirred at room temperature for 16 hours. Water was added to the reaction solution, extracted with ethyl acetate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography and purification (chloroform:methanol=100:00-90:10) to obtain tert-Butyl 3-(4-ethyl-2-(hydroxymethyl)-1-methyl-1H-imidazole-5-carboxylate (326 mg). (Step 4) Dissolve tert-butyl 3-(4-ethyl-2-(hydroxymethyl)-1-methyl-1H-imidazole-5-carboxylate (62.7 mg) obtained in the above step 3) Manganese dioxide (187 mg) was added to ethyl acetate (3 mL), and the mixture was heated and stirred at 100° C. for 50 minutes. The insoluble matter was filtered off with celite, and the filtrate was concentrated to obtain the title compound (55.4 mg).

Manufacturing example 41 Methyl 2-(1-((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)ethyl)-1-methyl-1H-imidazole-5-carboxy acid ester (Step 1) Dissolve methyl 3-methylimidazole-4-carboxylate (1.0 g) in dichloromethane (32 mL), cool to 0°C, and add triethylamine (4.4 mL) and ethyl chloride. Add chlorine (1.6 mL) and stir for 30 minutes. Water was added to the reaction solution, and the organic layer was separated, dried over magnesium sulfate, and concentrated. The obtained residue was subjected to column purification (hexane: ethyl acetate = 50:50-0:100), thereby obtaining methyl 2-(1-acetyloxyvinyl)-1-methyl-1H imidazole -5-carboxylate (0.40g). (Step 2) Dissolve the methyl 2-(1-acetyloxyvinyl)-1-methyl-1H imidazole-5-carboxylate (0.40g) obtained in the above step 1 in methanol (3 mL) , add ammonia solution (28%, 1mL). The reaction solution was stirred at room temperature for 30 minutes, then concentrated, and water and ethyl acetate were added. After the organic layer is separated, concentrated, and the obtained residue is subjected to column chromatography purification (hexane: ethyl acetate = 80:20-30:70), thereby obtaining methyl 2-acetyl-3-methyl Imidazole-4-carboxylate (0.19g). (Step 3) Dissolve the methyl 2-acetyl-3-methylimidazole-4-carboxylate (0.13g) obtained in the above step 2 in methanol (3.0mL), and add sodium borohydride (0.1g ) and stir at room temperature for 15 minutes. Acetone (1.0 mL) was added to the reaction liquid, and then concentrated. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated to obtain methyl 2-(1-hydroxyethyl)-3-methylimidazole-4-carboxylate. (Step 4) Dissolve the methyl 2-(1-hydroxyethyl)-3-methylimidazole-4-carboxylate obtained in the above step 3 in dichloromethane (3.0 mL), and add thionyl chloride (0.1 mL) and stirred at room temperature for 30 minutes. The reaction solution was poured into saturated baking soda water, and the obtained mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated, and the obtained residue was subjected to column purification (hexane:ethyl acetate=90:10-40:60), thereby obtaining methyl 2-(1-chloroethyl) -3-Methylimidazole-4-carboxylate (0.12g). (Step 5) Add the DMF (0.2 mL) solution of methyl 2-(1-chloroethyl)-3-methylimidazole-4-carboxylate (0.03 g) obtained in the above Step 4 to produce Production Example 1 The obtained 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (0.03g) and potassium carbonate (0.05g) were stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated, and the obtained residue was purified by column chromatography (hexane: ethyl acetate = 50:50-10:90), thereby obtaining the title compound (0.027g) .

Manufacturing example 42 Ethyl 3-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-methyl-1H-pyrazole- 5-carboxylate (Step 1) Add N-chlorosuccinimide (0.20g) to a solution of ethyl 1,3-dimethyl-1H-pyrazole-5-carboxylate (0.20g) in DMF (2.0mL). Stir at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate, and concentrated to obtain a crude form of ethyl 4-chloro-2,5-dimethyl-pyrazole-3-carboxylate (0.24 g). (Step 2) Dissolve the crude form of ethyl 4-chloro-2,5-dimethyl-pyrazole-3-carboxylate (0.24g) obtained in step 1 above in carbon tetrachloride (5mL), After adding N-bromosuccinimide (0.63g) and 2,2'-azobis(isobutyronitrile) (0.02g), the mixture was heated and refluxed for 3 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, and washed with water and sodium sulfite aqueous solution. After drying the organic layer over sodium sulfate, the obtained residue was purified by column chromatography (hexane:ethyl acetate=97:3-75:25), thereby obtaining ethyl 5-(bromomethyl)- 4-Chloro-2-methylpyrazole-3-carboxylate (0.10 g). (Step 3) To a solution of ethyl 5-(bromomethyl)-4-chloro-2-methylpyrazole-3-carboxylate (0.10 g) obtained in the above step 2 in acetonitrile (0.50 mL) was added 5-(tert-butyl)-6-chloro-1H-indazol-3-amine (0.023g) and potassium carbonate (0.05g) obtained in Production Example 1 were stirred at room temperature for 1 day. The reaction solution was diluted with ethyl acetate, and insoluble matter was filtered out. After the filtrate was concentrated, the obtained residue was subjected to column chromatography purification (hexane:ethyl acetate=97:3-40:60) to obtain the title compound (0.013g).

Manufacturing example 43 3-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-pyrazole-5-carboxy acid After using N-bromosuccinimide to replace N-chlorosuccinimide in Production Example 42 (Step 1), ethyl 3-(((5- (tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-bromo-1-methyl-1H-pyrazole-5-carboxylate (0.23g) Dissolve in 1,4-dioxane (1.0mL), add methylboronic acid (0.046g), potassium phosphate aqueous solution (2N, 0.10mL), and (1,1'-bis(diphenylphosphino)iron Xin) Palladium (II) dichloride dichloromethane adduct (0.004 g). After the reaction solution was stirred at 110°C for 15 hours, methylboronic acid (0.032g), potassium phosphate aqueous solution (2N, 0.60mL), and (1,1'-bis(diphenylphosphino)ironium)palladium were added (II) Dichloromethane adduct (0.003 g) was further stirred at 110° C. for 24 hours. After cooling the reaction solution to room temperature, hydrochloric acid (1N) was added to adjust the pH to 2. The obtained mixture was extracted with ethyl acetate, and the organic layer was separated, dried over sodium sulfate, and concentrated. The obtained residue was purified by reverse phase separation HPLC (water: acetonitrile (0.1% formic acid)) to obtain the title compound (2.1 mg).

Manufacturing example 44 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxylic acid (Step 1) To a solution of 1,4-dimethyl-1H-imidazole-5-carboxylic acid (3.0 g) in dichloromethane (80 mL), O-tert-butyl-N,N'-diisopropyl was added Isourea (15.0g), stir at 45°C overnight. O-tert-butyl-N,N'-diisopropylisourea (700 mg) was added to the reaction solution, and the mixture was stirred at 45°C for 9 hours. The insoluble matter was filtered off, and the solid was washed with hexane/ethyl acetate (2/1) (300 mL). The filtrate was concentrated, hexane/ethyl acetate (2/1) (90 mL) was added, and the precipitated solid was filtered off. The filtrate was concentrated, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 1,4-dimethyl-1H-imidazole-5-carboxylate (3.5 g). (Step 2) To a solution of tert-butyl 1,4-dimethyl-1H-imidazole-5-carboxylate (500 mg) obtained in the above step 1 in THF (5.0 mL) under a nitrogen atmosphere, add 2,2,6,6-Tetramethylpiperidine (0.65 mL) and cooled to -78°C. Butyllithium (1.55M hexane solution, 3.30 mL) was added dropwise to the reaction mixture, and the mixture was stirred at the same temperature for 3 hours. DMF (0.59 mL) was added, and the mixture was further stirred at -78°C for 1 hour. Water was added to the reaction mixture, and the temperature was raised to room temperature. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography purification (hexane: ethyl acetate = 100:0-80:20), thereby obtaining tert-butyl 2-formyl. -1,4-Dimethyl-1H-imidazole-5-carboxylate (246 mg). (Step 3) Dissolve tert-butyl 2-formyl-1,4-dimethyl-1H-imidazole-5-carboxylate (246 mg) obtained in the above step 2 in dichloromethane (3 mL) , mixed 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (245 mg), trifluoroacetic acid (168 μL), and sodium triacetyloxyborohydride (560 mg) obtained in Production Example 1. ) and stir at room temperature for 1 hour. Water and saturated sodium bicarbonate were added to the reaction mixture, extracted with ethyl acetate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography and purification (ethyl acetate:methanol=100:0-90 :10), thereby obtaining tert-butyl 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-di Methyl-1H-imidazole-5-carboxylate (355 mg). (Step 4) tert-butyl 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)- obtained in step 3 above 1,4-Dimethyl-1H-imidazole-5-carboxylate (257 mg) was dissolved in trifluoroacetic acid (2.0 mL). After 1 hour, the reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added. , 1N aqueous sodium hydroxide solution (595 μL), and separate the organic layer. The solvent was distilled off under reduced pressure to obtain the title compound (223 mg).

Manufacturing example 45 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1-methyl-1H- Imidazole-5-carboxylic acid (Step 1) Dissolve dimethyl 2-bromo-1H-imidazole-4,5-dicarboxylate (2.1g) in THF (13mL), add methanol (0.65mL) and triphenylphosphine (2.3g ). The obtained mixture was cooled in a water bath, and DIAD (1.7 mL) was slowly added. The reaction solution was stirred at room temperature for 20 minutes, and then water was added and concentrated. The obtained residue was subjected to column purification (hexane:ethyl acetate=95:5-30:70), thereby obtaining dimethyl 2-bromo-1-methylimidazole-4,5-dicarboxylate ( 2.1g). (Step 2) Dissolve dimethyl 2-bromo-1-methylimidazole-4,5-dicarboxylate (2.1g) obtained in step 1 above in THF (25 mL), and add at -78°C Diisobutylaluminum hydride (1M toluene solution, 10.5 mL), stir for 30 minutes. An aqueous sodium potassium tartrate solution (30%, 50 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated. The obtained residue was subjected to column chromatography and purification (hexane:ethyl acetate=70:30-20:80), thereby obtaining methyl 2-bromo-5-formyl-3-methylimidazole-4 - Carboxylic acid ester (1.2g). (Step 3) Dissolve the methyl 2-bromo-5-formyl-3-methylimidazole-4-carboxylate (1.2g) obtained in the above step 2 in dichloromethane (12mL), and place in the room Bis(2-methoxyethyl)aminosulfur trifluoride (3.6 mL) was added at warm temperature. The reaction solution was stirred at room temperature for 3 hours and then cooled in an ice bath. The reaction liquid was cooled to 0° C., water was added, and then extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated, and the obtained residue was purified by column chromatography (hexane:ethyl acetate=100:0-40:60), thereby obtaining methyl 2-bromo- 5-(difluoromethyl)-3-methylimidazole-4-carboxylate (1.1 g). (Step 4) Cool the solution of methyl 2-bromo-5-(difluoromethyl)-3-methylimidazole-4-carboxylate (0.79g) obtained in the above step 3 in THF (15 mL) to - 78°C, and isopropylmagnesium chloride (2MTHF solution, 0.75 mL) was added over 5 minutes. After the reaction solution was stirred at -78°C for 40 minutes, DMF (1.2 mL) was added, and the temperature was slowly raised to 0°C. A mixture of 2N hydrochloric acid (3.5 mL) and saturated aqueous ammonium chloride solution (30 mL) was added to the reaction liquid, and the mixture was extracted with ethyl acetate. After the organic layer is separated, it is dried with sodium sulfate, and the obtained residue is subjected to column chromatography purification (hexane: ethyl acetate = 100:0-50:50), thereby obtaining methyl 5-(difluoromethyl methyl)-2-formyl-3-methylimidazole-4-carboxylate (0.50 g). (Step 5) Methyl 5-(difluoromethyl)-2-formyl-3-methylimidazole-4-carboxylate (45 mg) obtained in the above Step 4 and 5 obtained in Production Example 1 -(tert-butyl)-6-chloro-1H-indazol-3-amine (49 mg) was dissolved in dichloromethane (1 mL), TFA (0.032 mL) was added, and stirred for 5 minutes. Sodium triacetyloxyborohydride (84 mg) was added to the resulting suspension, and the mixture was stirred for 30 minutes. The reaction solution was diluted with ethyl acetate, and washed with saturated sodium bicarbonate aqueous solution and water. The organic layer was separated, dried over sodium sulfate, and concentrated. The obtained residue was subjected to column chromatography purification (hexane:ethyl acetate=70:30-0:100), thereby obtaining methyl 2-(((5-(tert-butyl)-6-chloro -1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1-methyl-1H-imidazole-5-carboxylate (60 mg). (Step 6) Use the methyl 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-( A mixture of difluoromethyl)-1-methyl-1H-imidazole-5-carboxylate (244 mg), THF (5 mL), methanol (2.0 mL), and 2N aqueous sodium hydroxide solution (1.0 mL) was heated at room temperature. After stirring at low temperature for 30 minutes, 2N hydrochloric acid (1.1 mL) was added. The obtained mixture was extracted with ethyl acetate, and the organic layer was washed with brine (20%) and dried over sodium sulfate. The solvent was concentrated under reduced pressure to obtain a crude form of the title compound (251 mg).

Manufacturing example 46 tert-butyl 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-fluoro-1-methyl-1H-imidazole -5-carboxylate (Step 1) To a solution of methyl 4-fluoro-1H-imidazole-5-carboxylate (400 mg) obtained in Production Example 11 in THF (5 mL), methanol (120 μL), triphenylphosphine (870 mg) and DIAD were added (660 μL) and stir at room temperature for 30 min. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl 4-fluoro-1-methyl-1H-imidazole-5- Carboxylic acid ester (280 mg). (Step 2) Add 5N sodium hydroxide aqueous solution (1 mL) to the ethanol solution (2 mL) of methyl 4-fluoro-1-methyl-1H-imidazole-5-carboxylate (280 mg) obtained in the above step 1, Stir at room temperature for 1 hour. After the solution was distilled off under reduced pressure, 5N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solution was distilled off under reduced pressure to obtain crude 4-fluoro-1-methyl-1H-imidazole-5-carboxylic acid (237 mg). (Step 3) To a solution of 4-fluoro-1-methyl-1H-imidazole-5-carboxylic acid (237 mg) obtained in Step 2 above in THF (10 mL), 4-dimethylaminopyridine (400 mg) was mixed, Di-tert-butyl dicarbonate (720 mg) and stirred at 50°C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 0.5N aqueous sodium hydroxide solution, and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 4-fluoro-1-methyl-1H-imidazole- 5-carboxylate (233 mg). (Step 4) To a solution of tert-butyl 4-fluoro-1-methyl-1H-imidazole-5-carboxylate (233 mg) obtained in step 3 above in THF (12 mL) under a nitrogen atmosphere, add 2,2,6,6-Tetramethylpiperidine (0.811 mL) and cooled to -78°C. Butyllithium (1.55 M hexane solution, 3.78 mL) was added dropwise to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. DMF (0.47 mL) was added, and the mixture was further stirred at -78°C for 1 hour. Water and 10% phosphoric acid aqueous solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 4-fluoro-2-formyl-1-methyl. 1H-imidazole-5-carboxylate (84 mg). (Step 5) A solution of tert-butyl 4-fluoro-2-carboxyl-1-methyl-1H-imidazole-5-carboxylate (84 mg) obtained in step 4 above in dichloromethane (1 mL) 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (75 mg), trifluoroacetic acid (170 μL), and sodium triacetyloxyborohydride (142 mg) obtained in Production Example 1 were mixed. , and stir at room temperature for 15 minutes. An aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining the title compound (103 mg).

Manufacturing example 47 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-methyl-1H-imidazole-5-carboxy acid (Step 1) A carbon tetrachloride solution (20 mL) of methyl 4-chloro-1-methyl-1H-imidazole-5-carboxylate (1 g) obtained in Production Example 13 (Step 1) was dissolved in nitrogen. Under ambient air, N-bromosuccinimide (1.3 g) and azobisisobutyronitrile (120 mg) were mixed, and stirred at 95° C. overnight. After filtering the reaction mixture, the solution was distilled off under reduced pressure, and the crude product was subjected to column purification (hexane: ethyl acetate), thereby obtaining methyl 2-bromo-4-chloro-1-methyl-1H. - Imidazole-5-carboxylate (930 mg). (Step 2) A solution of methyl 2-bromo-4-chloro-1-methyl-1H-imidazole-5-carboxylate (730 mg) obtained in step 1 above in tetrahydrofuran (26 mL) at -78°C , a 2M solution of isopropylmagnesium chloride in tetrahydrofuran (3.5 mL) was added dropwise, and stirred at the same temperature for 1 hour. After N,N-dimethylformamide was added dropwise to the reaction mixture, the temperature was raised to -20°C and further stirred for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solution was distilled off under reduced pressure, and the crude substance was subjected to column purification (hexane: ethyl acetate), thereby obtaining methyl 4-chloro-2-formyl-1-methyl-1H-imidazole- 5-carboxylate (460 mg). (Step 3) Mix the solution of methyl 4-chloro-2-formyl-1-methyl-1H-imidazole-5-carboxylate (290 mg) obtained in step 2 above in dichloromethane (6 mL). 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (290 mg), trifluoroacetic acid (220 μL), and sodium triacetyloxyborohydride (550 mg) obtained in Production Example 1, and Stir at room temperature for 15 minutes. An aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl 2-(((5-(tert-butyl)-6 -Chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-methyl-1H-imidazole-5-carboxylate (430 mg). (Step 4) To the methyl 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro obtained in the above step 3 -A 5N aqueous sodium hydroxide solution (1 mL) was added to an ethanol solution (1 mL) of 1-methyl-1H-imidazole-5-carboxylate (85 mg) and stirred at room temperature for 1 hour. The reaction mixture was distilled off under reduced pressure, 5N hydrochloric acid was added, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solution was distilled off under reduced pressure to obtain the title compound (70 mg).

Manufacturing example 48 tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1-isopropyl-4-methyl 1H-imidazole-5-methamide)azetidine-1-carboxylate To tert-butyl 3-(2-formyl-1-isopropyl-4-methyl-1H-imidazole-5-formamide)azetidine-1-carboxylate obtained in Production Example 37 (148 mg) of dichloromethane (3.0 mL) was mixed with 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (86 mg) obtained in Production Example 1, trifluoroacetic acid (59 μL), Sodium triacetylborohydride (246 mg) and stirred at room temperature for 1 hour. Water was added to the reaction mixture, extracted with ethyl acetate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography and purification (ethyl acetate:methanol=100:0-80:20). This gave the title compound (140 mg).

Manufacturing example 49 tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H -imidazole-5-methamide) azetidine-1-carboxylate To tert-butyl 3-(2-formyl-1,4-dimethyl-1H-imidazole-5-formamide)azetidine-1-carboxylate (55.5 mg) obtained in Production Example 36 ), dichloromethane (4.0 mL) and trifluoroacetic acid (40 μL) were added to 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (33 mg) obtained in Production Example 1, and Sodium triacetylborohydride (60 mg). The mixture was stirred at room temperature for 35 minutes, and after stirring, a saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution. The organic layer was separated and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining the title compound (71.3 mg).

Manufacturing example 50 tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)- 1-Isopropyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (step 1) in DMF of 1H-imidazole-4,5-dicarboxylic acid dimethyl ester (13.5 g) (135 mL) potassium carbonate (20.3 g) and 2-iodopropane (24.9 g) were added to the solution, and the mixture was stirred at 50° C. for 9 hours. Saturated ammonium chloride and water were added to the reaction liquid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. Dry with sodium sulfate, remove the solvent by distillation under reduced pressure, and subject the obtained residue to column chromatography purification (hexane: ethyl acetate), thereby obtaining 1-isopropyl-1H-imidazole-4, 5-dicarboxylic acid dimethyl ester (16.3g). (Step 2) Cool the solution of 1-isopropyl-1H-imidazole-4,5-dicarboxylic acid dimethyl ester (16.3g) obtained in the above step 1 in THF (200mL) in a dry ice acetone bath, add 1M dimethyl Isobutylaluminum hydride in toluene (79.3 mL). After the reaction, an aqueous solution (200g) of Rochelle salt (100g) was added and stirred for 1 hour. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the solvent was distilled off to obtain 5-formyl-3-isopropylimidazole-4-carboxylic acid methyl ester (14.1 g). (Step 3) To a solution of 5-formyl-3-isopropylimidazole-4-carboxylic acid methyl ester (12.5 g) obtained in Step 2 above in dichloromethane (140 mL), bis(2-methoxy) was added Ethyl)aminosulfur trifluoride (53.0 mL) and stirred at 45°C for 100 minutes. The reaction solution was cooled in an ice bath, and water was slowly added. Extract with chloroform, dry with sodium sulfate, distill the solvent under reduced pressure, and perform column chromatography purification of the obtained residue (hexane: ethyl acetate) to obtain 4-(difluoromethyl) -1-Isopropyl-1H-imidazole-5-carboxylic acid methyl ester (10.3g). (Step 4) Add 5N hydroxide to a solution of 4-(difluoromethyl)-1-isopropyl-1H-imidazole-5-carboxylic acid methyl ester (10.3g) obtained in step 3 above in ethanol (150mL). aqueous sodium solution (52 mL) and stirred at room temperature for 30 minutes. The reaction solution was cooled in an ice bath, and 5N hydrochloric acid (80 mL) was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 4-(difluoromethyl)-1-isopropyl-1H-imidazole-5-carboxylic acid (9.64 g). (Step 5) To a solution of 4-(difluoromethyl)-1-isopropyl-1H-imidazole-5-carboxylic acid (9.64g) obtained in step 4 above in DMF (90 mL), 1-hydroxybenzo was added Triazole monohydrate (8.49g), 1-Boc-3-aminoazetidine (8.35mL), diisopropylethylamine (23.2mL), WSC hydrochloride (10.2g). React at 45°C for 9 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine. Dry with sodium sulfate, distill the solvent under reduced pressure, and perform column chromatography purification of the obtained residue (hexane: ethyl acetate) to obtain tert-butyl 3-(4-(difluoro) Methyl)-1-isopropyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (15.9 g). (Step 6) To tert-butyl 3-(4-(difluoromethyl)-1-isopropyl-1H-imidazole-5-methamide)azetidine-1-carboxylic acid obtained in step 5 above To the acid ester (5.0g), add THF (100mL) and 2,2,6,6-tetramethylpiperidine (11.9mL), cool it in a dry ice acetone bath, and add butyllithium (2.6M hexane solution for 15 minutes) , 33.0mL). The mixture was stirred for 1 hour while cooling in a dry ice acetone bath, DMF (1.32 mL) was added, and the mixture was further stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added and the temperature was raised to room temperature. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(4-(difluoromethyl)-2-formyl-1-isopropyl) -1H-imidazole-5-methamide)azetidine-1-carboxylate (3.55g). (Step 7) To tert-butyl 3-(4-(difluoromethyl)-2-formyl-1-isopropyl-1H-imidazole-5-formamide) acridine obtained in the above step 6 Butidine-1-carboxylate (1.00 g) and a THF (10 mL) solution of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (608 mg) obtained in Production Example 1 were added trifluoroacetic acid (396 μL) and stirred at room temperature for 30 min. Sodium triacetoxyborohydride (274 mg) was added three times at intervals of 20 minutes, and then the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled in an ice bath, and ethyl acetate and saturated aqueous sodium bicarbonate solution were added. The organic layer was separated and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining the title compound (1.48 g).

Manufacturing example 51 Methyl(R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole- 3-yl)amino)methyl)-4-chloro-1H-imidazole-5-carboxylate Methyl (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-2-formyl-1H-imidazole-5- obtained in Production Example 25 To a THF (30 mL) solution of carboxylic acid ester (2.16 g) and 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (1.34 g) obtained in Production Example 1, trifluoroacetic acid ( 1.00 mL) and stir at room temperature for 30 minutes. Sodium triacetylborohydride (600 mg) was added five times at intervals of 60 minutes, and then the mixture was stirred at room temperature for 80 minutes. Ethyl acetate and saturated sodium bicarbonate aqueous solution were added to the reaction solution, and the organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform:ethanol) and concentrated. The obtained solid was collected to obtain the title compound (2.81 g).

[Table 1]

[Table 2]

Example 1 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1-Methyl-1H-imidazole-5-methamide 5-(tert-butyl)-6-chloro-1H-indazol-3-amine (18.3 mg) obtained in Production Example 1 and N-(1-acrylyl azetidine) obtained in Production Example 35 To a solution of -3-yl)-2-formyl-1-methyl-1H-imidazole-5-formamide (26.0 mg) in dichloromethane (2.00 mL), trifluoroacetic acid (10 μL) was added, and trifluoroacetic acid (10 μL) was added. Sodium acetylborohydride (30 mg). After stirring at room temperature for 1 hour, saturated sodium bicarbonate aqueous solution and ethyl acetate were added to the reaction liquid. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform:ethanol) to obtain the title compound (25.2 mg).

Example 2 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-methylthiazole-5-methamide (Step 1) To a solution of 2-bromo-4-methylthiazole-5-carboxylic acid (500 mg) and 1-Boc-3-aminoazetidine (344 mg) in DMF (6.0 mL), add N,N-di Isopropylethylamine (1.0 mL), HATU (900 mg). After stirring at room temperature for 3 hours and 30 minutes, water and a 10% phosphoric acid aqueous solution were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(2-bromo-4-methylthiazole- 5-Formamide) azetidine-1-carboxylate (642 mg). (Step 2) Use tert-butyl 3-(2-bromo-4-methylthiazole-5-carboxamide) azetidine-1-carboxylate (642 mg) obtained in the above step 1, tributyl A solution of vinyltin (600 μL) and quaternary (triphenylphosphine)palladium (0) (60 mg) in 1,4-dioxane (10 mL) was stirred at 100°C overnight. The reaction solution was concentrated, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(4-methyl-2-vinylthiazole-5-carboxylic acid) Amine) azetidine-1-carboxylate (516 mg). (Step 3) 1, 2,6-lutidine (372 μL) and sodium periodate (1.37 g) were added to the 4-dioxane (12 mL) and water (3.0 mL) solutions, and then 1% osmium tetroxide aqueous solution (820 μL) was added. After stirring at room temperature for 4 hours, a sodium thiosulfate aqueous solution was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. After drying with sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to column chromatography and purification (chloroform:ethanol), thereby obtaining tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide) azetidine-1 -Carboxylic acid ester (336 mg). (Step 4) The tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide)azetidine-1-carboxylate obtained in the above-mentioned Step 3 was compared with Production Example 1 To the obtained solution of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (22 mg) in dichloromethane (2.00 mL), add trifluoroacetic acid (10 μL), and add triacetyl oxide Sodium borohydride (30 mg). After stirring at room temperature for 2 hours, saturated sodium bicarbonate aqueous solution and ethyl acetate were added to the reaction liquid. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(2-(((5-(tert- Butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-methylthiazole-5-carboxamide)aminoazetidine-1-carboxylate. (Step 5) To tert-butyl 3-(2-(((5-(tert-butyl))-6-chloro-1H-indazol-3-yl)amino)methyl obtained in the above step 4 )-4-Methylthiazole-5-carboxamide)aminoazetidine-1-carboxylate was added trifluoroacetic acid (1 mL). Trifluoroacetic acid was removed by distillation, and THF (4.0 mL), N,N-diisopropylethylamine (500 μL), and 1 M acrylic chloride acetonitrile solution (80 μL) were added. Saturated sodium bicarbonate aqueous solution and ethyl acetate were added to the reaction liquid. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform:ethanol) to obtain the title compound (12.5 mg).

Example 3 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1,4-Dimethyl-1H-imidazole-5-methamide In addition to using tert-butyl 3-(2-formyl-1,4-dimethyl-1H-imidazole-5-formamide)azetidine-1-carboxylate obtained in Production Example 36, Except for the tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide) azetidine-1-carboxylate used in Example 2 (step 4), the rest were carried out and implemented. The same method as in Example 2 (steps 4 and 5) was used to obtain the title compound (45.8 mg).

Example 4 N-(1-propenyl azedine-3-yl)-2-(1-((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)ethyl methyl)-1-methyl-1H-imidazole-5-carboxamide (Step 1) Methyl 2-(1-((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)ethyl)-1 obtained in Production Example 41 -To a solution of methyl-1H-imidazole-5-carboxylate (27 mg) in methanol (1.0 mL), 2N aqueous sodium hydroxide solution (0.5 mL) was added and stirred at room temperature for 20 minutes. 5N hydrochloric acid (0.2 mL) was added to the reaction solution, and the solvent was concentrated to obtain crude 2-[1-[(5-tert-butyl-6-chloro-1H-indazol-3-yl)amino]ethyl]- 3-Methyl-imidazole-4-carboxylic acid. (Step 2) To the crude 2-[1-[(5-tert-butyl-6-chloro-1H-indazol-3-yl)amino]ethyl]-3-methyl obtained in the above step 1 - Imidazole-4-carboxylic acid Add 1-(3-aminoazetidin-1-yl)prop-2-en-1-one hydrochloride (13.5 mg) obtained in Production Example 27 and DMF (2.0 mL) ), and further added N,N-diisopropylethylamine (56 μL) and HATU (32 mg). Purification by reverse phase separation HPLC (water: acetonitrile (0.1% formic acid)) gave the title compound (14 mg).

Example 5 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl- d2)-1,4-dimethyl-1H-imidazole-5-methamide (Step 1) The same method as in Production Example 36 (Step 2) was performed except that DMF-d7 was used instead of DMF used in Production Example 36 (Step 2), thereby obtaining tert-butyl 3-(2- (Formacyl-d)-1,4-dimethyl-1H-imidazole-5-formamide)azetidine-1-carboxylate (72.5 mg). (Step 2) To tert-butyl 3-(2-(formyl-d)-1,4-dimethyl-1H-imidazole-5-formamide)azetidine- obtained in the above step 1 1-carboxylic acid ester (36 mg), 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (22 mg) obtained in Production Example 1 were added with dichloromethane (4.0 mL) and trifluoride Acetic acid (30 μL), and sodium boron cyanodeuteride (24 mg) was added. After stirring at room temperature for 70 minutes, saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction liquid. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform:ethanol), thereby obtaining tert-butyl 3-(2-(((5-(tert-butyl)) -6-Chloro-1H-indazol-3-yl)amino)methyl-d2)-1,4-dimethyl-1H-imidazole-5-carboxamide)aminoazetidine-1-1 -Carboxylic acid ester (33.9 mg). (Step 3) In addition to using tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl obtained in the above step 2) Base-d2)-1,4-dimethyl-1H-imidazole-5-carboxamide)aminoazetidine-1-1-carboxylate (33.9 mg) was substituted for use in Example 2 (step 5) tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-methylthiazole-5- The title compound (24.2 mg) was obtained by carrying out the same method as in Example 2 (step 5) except formamide)aminoazetidine-1-carboxylate (D conversion rate: 75%).

Example 6 N-(1-propenyl azedine-3-yl)-3-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-methyl-1H-pyrazole-5-methamide Instead of using ethyl 3-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1- obtained in Production Example 42 Methyl-1H-pyrazole-5-carboxylate (12.6 mg) replaced the methyl 2-(1-((5-(tert-butyl)-6-chloro- Except for 1H-indazol-3-yl)amino)ethyl)-1-methyl-1H-imidazole-5-carboxylate, the same method as in Example 4 (steps 1, 2) was carried out. This gave the title compound (7.7 mg).

Example 7 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) Thiazole-4-methamide (Step 1) To the DMF (2.0 mL) solution of 2-ethoxycarbonylthiazole-4-carboxylic acid (319 mg) and 1-Boc-3-aminoazetidine (253 mg) obtained in Production Example 14, N was added , N-diisopropylethylamine (672μL), HATU (599mg). Stir at room temperature for 30 minutes, add water and ethyl acetate, and separate the organic layer. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining ethyl 4-((1-tert-butoxycarbonyl azetidine -3-yl)carbomethyl)thiazole-2-carboxylate (319 mg). (Step 2) Ethanol of ethyl 4-((1-tert-butoxycarbonylazetidin-3-yl)carbamomethyl)thiazole-2-carboxylate (319 mg) obtained in the above step 1 (5.0 mL) solution was added sodium borohydride (71.2 mg) and stirred at room temperature for 1 hour. 2N hydrochloric acid was added to the reaction liquid, the reaction liquid was concentrated, and ethyl acetate and saturated sodium bicarbonate aqueous solution were added to the obtained residue. The organic layer was separated and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate), thereby obtaining tert-butyl 3-((2-(hydroxymethyl)thiazole-4-carbonyl) )Amino)azetidine-1-carboxylate (260 mg). (Step 3) Ethyl acetate of tert-butyl 3-((2-(hydroxymethyl)thiazole-4-carbonyl)amino)azetidine-1-carboxylate (130 mg) obtained in the above step 2 Manganese dioxide (405 mg) was added to the ester (10 mL) solution and stirred at 100°C for 2 hours. The reaction liquid was filtered through celite, and the filtrate was concentrated to obtain tert-butyl 3-((2-methylthiazole-4-carbonyl)amino)azetidine-1-carboxylate (114 mg). (Step 4) In addition to using tert-butyl 3-[(2-methanothiazole-4-carbonyl)amino]azetidine-1-carboxylate (40.2 mg) obtained in the above step 3, in Example 2 (Step 4) Except for using tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide) azetidine-1-carboxylate, the rest is carried out as in Example 2 (Step 4, 5) The same method was used, whereby the title compound (26.6 mg) was obtained.

Example 8 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) Thiazole-5-methamide Except that 2-bromothiazole-5-carboxylic acid is used to replace the 2-bromo-4-methylthiazole-5-carboxylic acid used in Example 2 (Step 1), the rest is carried out as in Example 2 (Step 1-5 ), thereby obtaining the title compound (4.90 mg).

Example 9 N-(1-propenyl azedine-3-yl)-3-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1-Methyl-1H-pyrazole-5-methamide (Step 1) 3-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (150 mg) and 1-Boc-3-aminoazetidine (150 mg) obtained in Production Example 15 165 mg) in DMF (4.0 mL), add 1-hydroxybenzotriazole hydrate (140 mg), triethylamine (400 μL), and WSC hydrochloride (300 mg). After stirring at room temperature overnight, water and ethyl acetate were added. The organic layer was separated and washed with saturated brine. Dry with sodium sulfate, remove the solvent by distillation under reduced pressure, and perform column chromatography purification of the obtained residue (hexane: ethyl acetate) to obtain ethyl 5-((1-(tert-butanol) Oxycarbonyl)azetidin-3-yl)carbamocarbonyl)-1-methyl-1H-pyrazole-3-carboxylate (205 mg). (Step 2) To the ethyl 5-((1-(tert-butoxycarbonyl)azetidin-3-yl)aminomethyl)-1-methyl-1H-pyrazole obtained in the above step 1 -To a solution of 3-carboxylate (205 mg) in THF (3.0 mL), a 1 M solution of lithium boron hydride in THF (600 μL) was added, and stirred at 60° C. for 90 minutes. The reaction solution was cooled to room temperature, and saturated aqueous ammonium chloride solution and ethyl acetate were added. The organic layer was separated and washed with saturated brine. Dry with sodium sulfate, distill the solvent under reduced pressure, and perform column chromatography purification of the obtained residue (ethyl acetate:ethanol) to obtain tert-butyl 3-(3-(hydroxymethyl) )-1-Methyl-1H-pyrazole-5-methamide)azetidine-1-carboxylate (167 mg). (Step 3) In addition to using tert-butyl 3-(3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-methamide)azetidine-1-carboxylic obtained in step 2 above The acid ester (167 mg) was substituted for tert-butyl 3-((2-(hydroxymethyl)thiazole-4-carbonyl)amino)azetidine-1-carboxylate used in Example 7 (step 3). Except that, the same method as in Example 7 (step 3) was carried out, thereby obtaining tert-butyl 3-(3-formyl-1-methyl-1H-pyrazole-5-formamide) azedine Ridine-1-carboxylate (110 mg). (Step 4) In addition to using tert-butyl 3-(3-formyl-1-methyl-1H-pyrazole-5-formamide) azetidine-1-carboxylate obtained in the above step 3 (28 mg) substituted for tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide)azetidine-1-carboxylate used in Example 2 (step 4) , and the same method as in Example 2 (steps 4 and 5) was carried out to obtain the title compound (17.2 mg).

Example 10 N-(1-propenyl azedine-3-yl)-3-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1,4-Dimethyl-1H-pyrazole-5-methamide In addition to using 3-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl- obtained in Production Example 43 1H-pyrazole-5-carboxylic acid substituted the 2-[1-[(5-tert-butyl-6-chloro-1H-indazol-3-yl)amine group] used in Example 4 (step 2) The title compound (1.29 mg) was obtained by carrying out the same method as in Example 4 (step 2) except for ethyl]-3-methyl-imidazole-4-carboxylic acid.

Example 11 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Methyloxazole-5-methamide (Step 1) Except using 4-methyloxazole-5-carboxylic acid (1.00g) instead of 2-bromo-4-methylthiazole-5-carboxylic acid used in Example 2 (Step 1), the rest The same method as in Example 2 (step 1) was carried out, whereby tert-butyl 3-(4-methyloxazole-5-carboxamide) azetidine-1-carboxylate (1.64 g) was obtained. (Step 2) A solution of tert-butyl 3-(4-methyloxazole-5-carboxamide) azetidine-1-carboxylate (76 mg) obtained in the above Step 1 in THF (5.0 mL) Diisopropylamine (200 μL) was added and cooled under a dry ice acetone bath. Butyllithium (1.55M hexane solution, 0.60 mL) was added and stirred for 1 hour. The internal temperature was raised to -16 degrees, DMF (200 μL) was added, and the reaction solution was raised to room temperature and stirred overnight. Water and 10% phosphoric acid aqueous solution were added to the reaction liquid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(2-formyl-4-methyloxane). Azole-5-carboxamide) azetidine-1-carboxylate (42.2 mg). (Step 3) In addition to using tert-butyl 3-(2-formyl-4-methyloxazole-5-formamide) azetidine-1-carboxylate (42.2 mg) obtained in the above step 2 ) substituted for tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide) azetidine-1-carboxylate used in Example 2 (step 4), the rest The same method as in Example 2 (steps 4, 5) was carried out, whereby the title compound (41.5 mg) was obtained.

Example 12 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1-ethyl-4-methyl-1H-imidazole-5-carboxamide (Step 1) The same method as in Production Example 37 (Step 1-3) was performed except that ethanol was used instead of 2-propanol used in Production Example 37 (Step 1), thereby obtaining tert-butyl 3- (2-Formyl-1-ethyl-4-methyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (428 mg). (Step 2) In addition to using tert-butyl 3-(2-formyl-1-ethyl-4-methyl-1H-imidazole-5-formamide)azetidine-1 obtained in the above step 1 - Carboxylate (30.9 mg) substituted for tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide)azetidine-1- used in Example 2 (step 4) Except for the carboxylic acid ester, the same method as in Example 2 (steps 4 and 5) was carried out, whereby the title compound (18.0 mg) was obtained.

Example 13 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1-isopropyl-4-methyl-1H-imidazole-5-methamide In addition to using tert-butyl 3-(2-formyl-1-isopropyl-4-methyl-1H-imidazole-5-formamide)azetidine-1-carboxylic acid obtained in Production Example 37 The ester (91.0 mg) substituted for tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide)azetidine-1-carboxylate used in Example 2 (step 4) Except for this, the same method as in Example 2 (steps 4 and 5) was carried out, thereby obtaining the title compound (31.0 mg).

Example 14 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1-(2-methoxyethyl)-4-methyl-1H-imidazole-5-carboxamide Except for using 2-methoxyethanol instead of 2-propanol used in Production Example 37 (Step 1), the rest was carried out as in Production Example 37 (Steps 1-3), and then carried out as in Example 2 (Steps 4, 5). ), thereby obtaining the title compound (20.7 mg).

Example 15 N-(1-propenyl azetidin-3-yl)-1-benzyl-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine (methyl)methyl)-4-methyl-1H-imidazole-5-carboxamide Except using benzyl alcohol instead of 2-propanol used in Production Example 37 (Step 1), the same procedures as Production Example 37 (Step 1-3) and then Example 2 (Steps 4, 5) were carried out. method, whereby the title compound (30.2 mg) was obtained.

Example 16 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1-(2-(Dimethylamino)ethyl)-4-methyl-1H-imidazole-5-carboxamide Except that N,N-dimethylethanolamine was used instead of 2-propanol used in Production Example 37 (Step 1), the rest was carried out as in Production Example 37 (Step 1-3), and then carried out as in Example 2 (Step 4). , 5) The same method was used to obtain the title compound (9.0 mg).

Example 17 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1-Cyclopentyl-4-methyl-1H-imidazole-5-carboxamide Except using cyclopentanol instead of 2-propanol used in Production Example 37 (Step 1), the same procedures as Production Example 37 (Step 1-3) and then Example 2 (Steps 4, 5) were carried out. method, whereby the title compound (20.5 mg) was obtained.

Example 18 N-(1-propenyl azedine-3-yl)-1-butyl 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-methyl-1H-imidazole-5-methamide Except that 1-butanol is used instead of 2-propanol used in Production Example 37 (Step 1), the rest is carried out as in Production Example 37 (Step 1-3), and then the same as in Example 2 (Steps 4, 5). method, thereby obtaining the title compound (18.3 mg).

Example 19 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Methyl-1-propyl-1H-imidazole-5-methamide Except that 1-propanol is used instead of 2-propanol used in Production Example 37 (Step 1), the rest is carried out as in Production Example 37 (Step 1-3), and then the same as Example 2 (Steps 4, 5). method, thereby obtaining the title compound (20.5 mg).

Example 20 N-(1-propenyl azedine-3-yl)-1-(sec-butyl)-2-((5-(tert-butyl)-6-chloro-1H-indazole-3 -yl)amino)methyl)-4-methyl-1H-imidazole-5-methamide Except that 2-butanol is used instead of 2-propanol used in Production Example 37 (Step 1), the rest is carried out as in Production Example 37 (Steps 1-3), and then the same as in Example 2 (Steps 4, 5). method, thereby obtaining the title compound (26.3 mg).

Example 21 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1-(Difluoromethyl)-4-methyl-1H-imidazole-5-methamide (Step 1) A suspension of ethyl 4-methyl-1H-imidazole-5-carboxylate (2.0g) and sodium chlorodifluoroacetate (2.98g) in 2-propanol was heated to 150°C using a microwave reaction device. After 45 minutes, the internal pressure increased and the device stopped. Therefore, after slowly opening and reducing the pressure, the reaction was carried out at 150°C for 16 hours again. Insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining 1-(difluoromethyl)-4-methyl. -1H-imidazole-5-carboxylic acid ethyl ester (290 mg). (Step 2) To the ethanol (5.0 mL) solution of 1-(difluoromethyl)-4-methyl-1H-imidazole-5-carboxylic acid ethyl ester (328 mg) obtained in the above step 1, add paraformaldehyde ( 735mg), and use a microwave reaction device to react at 160°C for 20 hours. The reaction solution was concentrated, and the obtained residue was subjected to column chromatography and purification (hexane: ethyl acetate: methanol), thereby obtaining 1-(difluoromethyl)-2-(hydroxymethyl)-4-methyl Ethyl-1H-imidazole-5-carboxylate (55.7 mg). (Step 3) Ethanol (55.7 mg) of 1-(difluoromethyl)-2-(hydroxymethyl)-4-methyl-1H-imidazole-5-carboxylic acid ethyl ester (55.7 mg) obtained in the above step 2 2.0 mL) solution was added with 4N aqueous sodium hydroxide solution (90 μL) and stirred at room temperature overnight. 6N hydrochloric acid (60 μL) was added to the reaction solution, and the solvent was concentrated to obtain crude 1-(difluoromethyl)-2-(hydroxymethyl)-4-methyl-1H-imidazole-5-carboxylic acid. (Step 4) Add 1-Boc-3-amine to the crude 1-(difluoromethyl)-2-(hydroxymethyl)-4-methyl-1H-imidazole-5-carboxylic acid obtained in the above step 3. Azetidine (62mg), 1-hydroxybenzotriazole hydrate (36.6mg), DMF (1.0mL), N,N-diisopropylethylamine (121μL), WSC hydrochloride (96.0mg ). After stirring at room temperature for 3 days, water and ethyl acetate were added. The organic layer is separated, the solvent is distilled off under reduced pressure, and the obtained residue is subjected to column chromatography and purification (chloroform:methanol), thereby obtaining tert-butyl 3-(1-(difluoromethyl)- 2-(hydroxymethyl)-4-methyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (80.0 mg). (Step 5) In addition to using tert-butyl 3-(1-(difluoromethyl)-2-(hydroxymethyl)-4-methyl-1H-imidazole-5-carboxamide obtained in step 4 above) ) azedine-1-carboxylate (23.0 mg) substituted for tert-butyl 3-((2-(hydroxymethyl)thiazole-4-carbonyl)amine) acridine used in Example 7 (step 3) Except for butidine-1-carboxylate, the same method as in Example 7 (step 3) was carried out to obtain tert-butyl 3-(1-(difluoromethyl)-2-formyl- 4-Methyl-1H-imidazole-5-methamide)azetidine-1-carboxylate (20.3 mg). (Step 6) In addition to using tert-butyl 3-(1-(difluoromethyl)-2-formyl-4-methyl-1H-imidazole-5-formamide) acridine obtained in step 5 above Butidine-1-carboxylate (20.3 mg) replaced tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide) azedine used in Example 2 (step 4) The title compound (3.2 mg) was obtained by carrying out the same method as in Example 2 (steps 4 and 5) except for the ester of pyridine-1-carboxylate.

Example 22 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Methyl-1-(2,2,2-trifluoroethyl)-1H-imidazole-5-carboxamide Except for the substitution using 2-(hydroxymethyl)-4-methyl-1-(2,2,2-trifluoroethyl)-1H-imidazole-5-carboxylic acid (162 mg) obtained in Production Example 22, Except for the use of 1-(difluoromethyl)-2-(hydroxymethyl)-4-methyl-1H-imidazole-5-carboxylic acid in Example 21 (step 4), the rest were carried out as in Example 21 (step 4). -6) The same method, whereby the title compound (25.7 mg) was obtained.

Example 23 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1-Cyclopropyl-4-methyl-1H-imidazole-5-carboxamide In addition to using 1-cyclopropyl-4-methyl-1H-imidazole-5-carboxylic acid obtained in Production Example 20 instead of 1,4-dimethyl-1H-imidazole- used in Production Example 36 (Step 1) Except for 5-carboxylic acid, the same method as Production Example 36 (Steps 1, 2) and then Example 2 (Steps 4, 5) was carried out to obtain the title compound (12.2 mg).

Example 24 N-(1-propenyl azedine-3-yl)-1-(tert-butyl)-2-((5-(tert-butyl)-6-chloro-1H-indazole-3 -yl)amino)methyl)-4-methyl-1H-imidazole-5-methamide In addition to using 1-(tert-butyl)-4-methyl-1H-imidazole-5-carboxylic acid obtained in Production Example 21 instead of 1,4-dimethyl-1H used in Production Example 36 (Step 1) Except for -imidazole-5-carboxylic acid, the same method as Production Example 36 (Steps 1, 2) and then Example 2 (Steps 4, 5) was carried out to obtain the title compound (35.0 mg).

Example 25 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1-Methyl-4-(trifluoromethyl)-1H-imidazole-5-methamide (Step 1) Mix 2-(diethoxymethyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid (220 mg) obtained in Production Example 16 to produce 1-(3-Aminoazetidin-1-yl)prop-2-en-1-one hydrochloride (240 mg) and DMF (2.0 mL) obtained in Example 27 were further added with N,N-diisopropyl Ethylamine (770 μL), HATU (570 mg). After stirring at room temperature for 1 hour, water (1 mL) was added, and the solvent was distilled off. Water and ethyl acetate were added to the obtained residue. The organic layer was separated and washed with saturated brine. After drying with sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining N-(1-acrylyl azetidine- 3-yl)-2-(diethoxymethyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole-5-carboxamide (190 mg). (Step 2) N-(1-acrylyl azetidine-3-yl)-2-(diethoxymethyl)-1-methyl-4-(trifluoromethyl) obtained in the above-mentioned step 1 (1H-imidazole-5-carboxamide) (180 mg), THF (5.5 mL), water (3.9 mL), and trifluoroacetic acid (560 μL) were added, and the mixture was stirred at 45°C for 4 hours. Ethyl acetate was added to the reaction liquid. The organic layer was separated and washed with saturated sodium bicarbonate aqueous solution and saturated brine. Dry with sodium sulfate, and distill the solvent under reduced pressure to obtain N-(1-acrylyl azedine-3-yl)-2-formyl-1-methyl-4-(trifluoromethyl (1H-imidazole-5-carboxamide) (170 mg). (Step 3) In addition to using N-(1-acrylyl azetidin-3-yl)-2-formyl-1-methyl-4-(trifluoromethyl)-1H obtained in the above-mentioned step 2 - Imidazole-5-formamide (40 mg) substituted for N-(1-acrylyl azetidin-3-yl)-2-formamide-1-methyl-1H-imidazole used in Example 1- Except for 5-formamide, the same method as in Example 1 was carried out to obtain the title compound (20.6 mg).

Example 26 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-iodo-1-methyl-1H-imidazole-5-methamide (Step 1) 5-(tert-butyl)-6-chloro-1H-indazol-3-amine (35.8 mg) obtained in Production Example 1 and methyl 2-formyl group obtained in Production Example 26 -To a solution of 4-iodo-1-methyl-1H-imidazole-5-carboxylate (47 mg) in dichloromethane (1.00 mL), trifluoroacetic acid (30 μL) was added, and sodium triacetyloxyborohydride ( 35mg). After stirring at room temperature for 1 hour, water was added to the reaction solution, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate) to obtain methyl 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-iodo-1-methyl-1H-imidazole-5-carboxy acid ester (23 mg). (Step 2) In addition to using the methyl 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4- obtained in the above-mentioned step 1 Iodo-1-methyl-1H-imidazole-5-carboxylate (23 mg) replaced the methyl 2-(1-((5-(tert-butyl)-6-) used in Example 4 (step 1) Except for chloro-1H-indazole-3-yl)amino)ethyl)-1-methyl-1H-imidazole-5-carboxylate, the same method as in Example 4 (steps 1, 2) was carried out. , thereby obtaining the title compound (8.2 mg).

Example 27 N-(1-propenyl azetidin-3-yl)-4-bromo-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-1-methyl-1H-imidazole-5-methamide (Step 1) 4-bromo-1-methyl-2-vinyl-1H-imidazole-5-carboxylic acid (840 mg) and 1-Boc-3-aminoazetidine (759 mg) obtained in Production Example 18 ) in dichloromethane (9.0 mL) were added 1-hydroxybenzotriazole hydrate (744 mg), N,N-diisopropylethylamine (1.25 mL), and WSC hydrochloride (1.06 g). After stirring at room temperature for 1 hour, water and ethyl acetate were added. The organic layer was separated and washed with saturated brine. Dry with sodium sulfate, distill the solvent under reduced pressure, and subject the obtained residue to column chromatography purification (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(4-bromo-1) -Methyl-2-vinyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (1.38 g). (Step 2) In addition to using tert-butyl 3-(4-bromo-1-methyl-2-vinyl-1H-imidazole-5-methamide)azetidine-1-carboxylic obtained in step 1 above The acid ester (35 mg) was substituted for tert-butyl 3-(4-methyl-2-vinylthiazole-5-carboxylic acid ester) azetidine-1-carboxylate used in Example 2 (step 3). Except for this, the same method as in Example 2 (step 3-5) was carried out, whereby the title compound (8.0 mg) was obtained.

Example 28 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-cyano-1-methyl-1H-imidazole-5-methamide (Step 1) Add 4-cyano-1-methyl-1H-imidazole-5-carboxylic acid (252 mg), 1-Boc-3-aminoazetidine (400 mg) and DMF ( 3.0 mL), further added N,N-diisopropylethylamine (750 μL) and HATU (750 mg), and stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated and washed with saturated brine. After drying with sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(4-cyano- 1-Methyl-1H-imidazole-5-methamide)azetidine-1-carboxylate (263 mg). (Step 2) tert-butyl 3-(4-cyano-1-methyl-1H-imidazole-5-carboxamide) azetidine-1-carboxylate obtained in the above step 1 (263 mg) , THF (7.0 mL), and 2,2,6,6-tetramethylpiperidine (600 μL) were cooled in a dry ice acetone bath, and butyllithium (1.55 M hexane solution, 2.0 mL) was added every 15 minutes. After stirring for 2 hours while cooling in a dry ice acetone bath, DMF (350 μL) was added, and the mixture was further stirred for 1 hour. Add water and 10% phosphoric acid aqueous solution, and warm to room temperature. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to column chromatography purification (chloroform:ethanol), thereby obtaining tert-butyl 3-(4-cyano-2-formyl-1-methyl-1H-imidazole-5-methyl amide) azetidine-1-carboxylate (199 mg). (Step 3) In addition to using tert-butyl 3-(4-cyano-2-formamide-1-methyl-1H-imidazole-5-formamide)azetidine-1 obtained in the above step 2 - Carboxylic acid ester (54 mg) substituted for tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide)azetidine-1-carboxylic acid used in Example 2 (step 4) acid ester, and the same method as in Example 2 (steps 4, 5) was carried out to obtain the title compound (27.3 mg).

Example 29 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-methyl-1H-imidazole-5-methamide (Step 1) Mix 2,4-dichloro-1-methyl-1H-imidazole-5-carbaldehyde (500mg), sulfamic acid (542mg) with 1,4-dioxane (20mL), water (20mL) ) was added to the mixed solution, and stirred at room temperature for 30 minutes. 10% phosphoric acid aqueous solution and ethyl acetate were added, and the organic layer was separated and washed with saturated brine. The mixture was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2,4-dichloro-1-methyl-1H-imidazole-5-carboxylic acid (536 mg). (Step 2) In addition to using 2,4-dichloro-1-methyl-1H-imidazole-5-carboxylic acid (536 mg) obtained in the above-mentioned Step 1 instead of the 2-bromo- 4-methylthiazole-5-carboxylic acid, and otherwise the same method as in Example 2 (step 1-5) was carried out, thereby obtaining the title compound (63 mg).

Example 30 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Fluoro-1-methyl-1H-imidazole-5-methamide (Step 1) In addition to using the methyl 4-fluoro-1H-imidazole-5-carboxylate obtained in Production Example 11 instead of the methyl 4-chloro-1H-imidazole-5- used in Production Example 38 (Step 1) For the carboxylic acid ester, methanol was used instead of 2-propanol, and the rest was carried out in the same manner as in Production Example 38 (step 1-4), thereby obtaining tert-butyl 3-(4-fluoro-2-methyl-1- Methyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (150 mg). (Step 2) In addition to using tert-butyl 3-(4-fluoro-2-formyl-1-methyl-1H-imidazole-5-formamide)azetidine-1- obtained in the above step 1 Carboxylate (75 mg) substituted for tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide)azetidine-1-carboxylic acid used in Example 2 (step 4) Except for the ester, the same method as in Example 2 (steps 4 and 5) was carried out to obtain the title compound (55.0 mg).

Example 31 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-ethyl-1-methyl-1H-imidazole-5-carboxamide In addition to using tert-butyl 3-(4-ethyl-2-formyl-1-methyl-1H-imidazole-5-formamide)azetidine-1-carboxylate obtained in Production Example 40 (55.4 mg) substituted for tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide)azetidine-1-carboxylate used in Example 2 (Step 4) Except for this, the same method as in Example 2 (steps 4 and 5) was carried out to obtain the title compound (30.5 mg).

Example 32 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1-isopropyl-4-(trifluoromethyl)-1H-imidazole-5-carboxamide (Step 1) 1-isopropyl-4-(trifluoromethyl)-2-vinyl-1H-imidazole-5-carboxylic acid (224 mg) and 1-Boc-3-amine obtained in Production Example 17 To a solution of azetidine (190 mg) in DMF (3.0 mL), N,N-diisopropylethylamine (190 μL) and HATU (380 mg) were added. Stir at room temperature for 1 hour, add water and ethyl acetate, and separate the organic layer. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(1-isopropyl-4-(tert-butyl) Fluoromethyl)-2-vinyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (359 mg). (Step 2) In addition to using tert-butyl 3-(1-isopropyl-4-(trifluoromethyl)-2-vinyl-1H-imidazole-5-carboxamide) acridine obtained in the above step 1 Butidine-1-carboxylate (49.5 mg) was substituted for tert-butyl 3-(4-methyl-2-vinylthiazole-5-methamide)azetidine used in Example 2 (Step 3) Except for -1-carboxylic acid ester, the same method as in Example 2 (step 3-5) was carried out, thereby obtaining the title compound (28.8 mg).

Example 33 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-(difluoromethyl)-1-isopropyl-1H-imidazole-5-methamide Instead of using tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4 obtained in Production Example 50 -(Difluoromethyl)-1-isopropyl-1H-imidazole-5-methamide)azetidine-1-carboxylate (1.48g) substituted for tert- used in Example 2 (step 5) Butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-methylthiazole-5-carboxamide ) aminoazetidine-1-carboxylate, the same method as in Example 2 (step 5) was carried out, thereby obtaining the title compound (503 mg).

Example 34 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Fluoro-1-isopropyl-1H-imidazole-5-methamide (Step 1) In addition to using the methyl 4-fluoro-1H-imidazole-5-carboxylate obtained in Production Example 11 instead of the methyl 4-chloro-1H-imidazole-5- used in Production Example 38 (Step 1) Except for the carboxylic acid ester, the same method as in Production Example 38 (step 1-4) was carried out to obtain tert-butyl 3-(4-fluoro-2-methanoyl-1-isopropyl-1H- Imidazole-5-carboxamide) azetidine-1-carboxylate (150 mg). (Step 2) In addition to using tert-butyl 3-(4-fluoro-2-formyl-1-isopropyl-1H-imidazole-5-formamide)azetidine-1 obtained in the above step 1 - Carboxylate (107 mg) substituted for tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide)azetidine-1-carboxylic acid used in Example 2 (step 4) Except for the acid ester, the same method as in Example 2 (steps 4 and 5) was carried out to obtain the title compound (65 mg).

Example 35 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-isopropyl-1H-imidazole-5-methamide In addition to using tert-butyl 3-(4-chloro-2-formyl-1-isopropyl-1H-imidazole-5-formamide)azetidine-1-carboxylate obtained in Production Example 38 (111 mg) substituted for tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide)azetidine-1-carboxylate used in Example 2 (step 4) , and the same method as in Example 2 (steps 4 and 5) was carried out to obtain the title compound (64 mg).

Example 36 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl- d2)-4-(difluoromethyl)-1-isopropyl-1H-imidazole-5-carboxamide (Step 1) The same method as in Production Example 50 (Step 6) was performed except that DMF-d7 was used instead of DMF used in Production Example 50 (Step 6), thereby obtaining tert-butyl 3-(4- (Difluoromethyl)-2-(formyl-d)-1-isopropyl-1H-imidazole-5-formamide)azetidine-1-carboxylate (165 mg). (Step 2) To tert-butyl 3-(4-(difluoromethyl)-2-(formyl-d)-1-isopropyl-1H-imidazole-5-methyl obtained in the above step 1) Methanol-d4 was added to amide) azetidine-1-carboxylate (77 mg) and 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (35 mg) obtained in Production Example 1. (1 mL) and dissolved, then the solvent was distilled off under reduced pressure. Methanol-d4 (1 mL) was added to the obtained residue again and dissolved, and then the solvent was distilled off under reduced pressure. To the obtained residue were added dichloromethane (3.0 mL), trifluoroacetic acid-d (40 μL), and sodium boron cyanodeuteride (22 mg). After stirring at room temperature for 50 minutes, saturated sodium bicarbonate aqueous solution and ethyl acetate were added to the reaction liquid. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform:ethanol), thereby obtaining tert-butyl 3-(2-(((5-(tert-butyl)) -6-Chloro-1H-indazol-3-yl)amino)methyl-d2)-4-(difluoromethyl)-1-isopropyl-1H-imidazole-5-carboxamide)acetin Ridine-1-carboxylate (67.8 mg). (Step 3) In addition to using tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl obtained in the above step 2) Base-d2)-4-(difluoromethyl)-1-isopropyl-1H-imidazole-5-methamide)azetidine-1-carboxylate (67.8 mg) was substituted in Example 2 (step 5) Used tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-methylthiazole Except for -5-formamide)aminoazetidine-1-carboxylate, the same method as in Example 2 (step 5) was carried out to obtain the title compound (45.0 mg) (D conversion rate > 95 %).

Example 37 N-(1-propenyl azedine-3-yl)-2-(((6-chloro-5-methyl-1H-indazol-3-yl)amino)methyl)-1-methyl Base-1H-imidazole-5-methamide In addition to using 6-chloro-5-methyl-1H-indazole-3-amine obtained in Production Example 5 instead of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine used in Example 1 Except for 3-amine, the same method as in Example 1 was carried out, thereby obtaining the title compound (15.9 mg).

Example 38 N-(1-propenyl azedine-3-yl)-2-(((6-chloro-5-vinyl 1H-indazol-3-yl)amino)methyl)-1-methyl -1H-imidazole-5-methamide In addition to using 6-chloro-5-vinyl-1H-indazole-3-amine obtained in Production Example 2 instead of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine used in Example 1 Except for 3-amine, the same method as in Example 1 was carried out, whereby the title compound (14.8 mg) was obtained.

Example 39 N-(1-propenyl azedine-3-yl)-2-(((6-chloro-5-ethyl-1H-indazol-3-yl)amino)methyl)-1-methyl Base-1H-imidazole-5-methamide In addition to using 6-chloro-5-ethyl-1H-indazole-3-amine obtained in Production Example 3 instead of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine used in Example 1 Except for 3-amine, the same method as in Example 1 was carried out, thereby obtaining the title compound (35.2 mg).

Example 40 N-(1-propenyl azetidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-pyrazolo[4,3-b]pyridine-3 -yl)amino)methyl)-1-methyl-1H-imidazole-5-methamide In addition to using 5-(tert-butyl)-6-chloro-1H-pyrazolo[4,3-b]pyridin-3-amine obtained in Production Example 4 instead of 5-(tert- The title compound (21.4 mg) was obtained by carrying out the same method as in Example 1 except for butyl)-6-chloro-1H-indazol-3-amine.

Example 41 N-(1-Acrylyl azedine-3-yl)-2-(((5-(tert-butyl)-6-methyl-1H-indazol-3-yl)amino)methyl )-1,4-dimethyl-1H-imidazole-5-methamide In addition to using 5-(tert-butyl)-6-methyl-1H-indazole-3-amine obtained in Production Example 6 instead of 5-(tert-butyl)- used in Example 2 (step 4) 6-chloro-1H-indazole-3-amine, and tert-butyl 3-(2-formyl-1,4-dimethyl-1H-imidazole-5-formyl) obtained in Production Example 36 was used Except for amine) azetidine-1-carboxylate substituted tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide) azetidine-1-carboxylate, the rest The same method as in Example 2 (steps 4, 5) was carried out, whereby the title compound (18.6 mg) was obtained.

Example 42 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-1H-indazol-3-yl)amino)methyl)-1-iso Propyl-4-methyl-1H-imidazole-5-methamide In addition to using 5-(tert-butyl)-1H-indazole-3-amine obtained in Production Example 7 instead of 5-(tert-butyl)-6-chloro-1H used in Example 2 (step 4) -Indazole-3-amine, using tert-butyl 3-(2-formyl-1-isopropyl-4-methyl-1H-imidazole-5-formamide) obtained in Production Example 37 Except for azetidine-1-carboxylate replacing tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide) azetidine-1-carboxylate, the rest are carried out with The same method as in Example 2 (steps 4 and 5) was used to obtain the title compound (29.1 mg).

Example 43 N-(1-propenyl azedine-3-yl)-4-chloro-2-(((6-chloro-5-(3,3,3-trifluoroprop-1-en-2-yl) )-1H-indazol-3-yl)amino)methyl)-1-isopropyl-1H-imidazole-5-methamide In addition to using 6-chloro-5-(3,3,3-trifluoroprop-1-en-2-yl)-1H-indazole-3-amine obtained in Production Example 8, the method in Example 2 (Step 4 ) using 5-(tert-butyl)-6-chloro-1H-indazol-3-amine, and using tert-butyl 3-(4-chloro-2-formyl-) obtained in Production Example 38 1-isopropyl-1H-imidazole-5-formamide) azedine-1-carboxylate substituted tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide) ) azetidine-1-carboxylate, the same method as in Example 2 (steps 4, 5) was carried out to obtain the title compound (8.0 mg).

Example 44 N-(1-propenyl azetidin-3-yl)-4-chloro-2-(((6-chloro-5-(1-(trifluoromethyl)cyclopropyl))-1H-indazole -3-yl)amino)methyl)-1-isopropyl-1H-imidazole-5-carboxamide In addition to using 6-chloro-5-(1-(trifluoromethyl)cyclopropyl)-1H-indazole-3-amine obtained in Production Example 9 instead of 5-( used in Example 2 (Step 4) tert-butyl)-6-chloro-1H-indazol-3-amine, and tert-butyl 3-(4-chloro-2-formyl-1-isopropyl-) obtained in Production Example 38 was used 1H-imidazole-5-formamide)azetidine-1-carboxylate substituted tert-butyl 3-(2-formamide-4-methylthiazole-5-formamide)azetidine-1 - Except for the carboxylic acid ester, the same method as in Example 2 (steps 4, 5) was carried out, whereby the title compound (10.0 mg) was obtained.

Example 45 N-(1-propenyl azedine-3-yl)-4-chloro-2-(((6-chloro-5-isopropyl-1H-indazol-3-yl)amino)methyl )-1-isopropyl-1H-imidazole-5-methamide In addition to using 6-chloro-5-isopropyl-1H-indazol-3-amine obtained in Production Example 10 instead of 5-(tert-butyl)-6-chloro- used in Example 2 (step 4) 1H-indazole-3-amine, and tert-butyl 3-(4-chloro-2-formyl-1-isopropyl-1H-imidazole-5-formamide) obtained in Production Example 38 was used Except for azetidine-1-carboxylate replacing tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide) azetidine-1-carboxylate, the rest are carried out with The same method as in Example 2 (steps 4 and 5) was used to obtain the title compound (23.3 mg).

Example 46 N-(1-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H- Imidazole-5-carbonyl)azetidin-3-yl)acrylamide (Step 1) 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-di To a solution of methyl-1H-imidazole-5-carboxylic acid (18.9 mg) and 3-N-BOC-aminoazetidine (22.9 mg) in DMF (1.5 mL), 1-hydroxybenzotriazole hydrate (10.0 mg), N,N-diisopropylethylamine (42.7 μL), WSC hydrochloride (21.6 mg). After stirring at room temperature overnight, water and ethyl acetate were added. The organic layer was separated and washed with saturated brine. Dry with sodium sulfate, remove the solvent by distillation under reduced pressure, and perform column chromatography purification of the obtained residue (ethyl acetate:methanol) to obtain tert-butyl (1-(2-(((((ethyl acetate:methanol)) 5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carbonyl)azetidine-3 -carbamate (24.8 mg). (Step 2) To tert-butyl (1-(2-(((5-(tert-butyl))-6-chloro-1H-indazol-3-yl)amino)methyl obtained in the above step 1 Trifluoroacetic acid (1.5 mL) was added to ethyl)-1,4-dimethyl-1H-imidazole-5-carbonyl)azetidin-3-yl)carbamate (24.8 mg). After stirring at room temperature for 10 minutes, the reaction solution was concentrated. THF (2.0 mL) and N,N-diisopropylethylamine (159 μL) were added to the obtained residue, and then, an acetonitrile solution (100 μL) containing acrylonitrile chloride (3.78 μL) was added. After stirring at room temperature for 15 minutes, methanol (2.0 mL) was added to the reaction liquid, and the reaction liquid was concentrated. The obtained residue was subjected to column chromatography purification (ethyl acetate:methanol) to obtain the title compound (10.4 mg).

Example 47 N-(1-acrylylpiperidin-4-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)- 1,4-dimethyl-1H-imidazole-5-methamide Except that 1-(4-aminopiperidin-1-yl)prop-2-en-1-one hydrochloride (9.7 mg) was used instead of the 3-N-BOC-amine used in Example 46 (step 1). Except for azetidine, the same method as in Example 46 (step 1) was carried out, whereby the title compound (21.4 mg) was obtained.

Example 48 N-(1-Acrylylpyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)- 1,4-dimethyl-1H-imidazole-5-methamide (Step 1) Except using tert-butyl 3-aminopyrrolidine-1-carboxylate (9.5 mg) instead of 3-N-BOC-aminoazetidine used in Example 46 (Step 1) , the rest is carried out in the same manner as in Example 46 (step 1), thereby obtaining tert-butyl 3-(2-(((5-(tert-butyl))-6-chloro-1H-indazole-3- (yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide)pyrrolidine-1-carboxylate (27.5 mg). (Step 2) To tert-butyl 3-(2-(((5-(tert-butyl))-6-chloro-1H-indazol-3-yl)amino)methyl obtained in the above step 1 )-1,4-dimethyl-1H-imidazole-5-carboxamide)pyrrolidine-1-carboxylate (27.5 mg), add chloroform (1.0 mL) and trifluoroacetic acid (0.5 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated. THF (1.0 mL) and N,N-diisopropylethylamine (129 μL) were added to the obtained residue, the reaction solution was cooled in an ice bath, and acrylic anhydride (5.4 μL) was added. After stirring for 15 minutes, water and ethyl acetate were added to the reaction liquid, and the organic layer was separated. After washing with saturated brine, drying over sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography purification (chloroform:methanol) to obtain the title compound (16.6 mg).

Example 49 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -N,1,4-trimethyl-1H-imidazole-5-carboxamide Except that tert-butyl 3-(methylamino)azetidine-1-carboxylate (9.5 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1). Except for this, the same method as in Example 46 (steps 1 and 2) was carried out to obtain the title compound (15.0 mg).

Example 50 1-(4-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H- Imidazole-5-carbonyl)piperazin-1-yl)prop-2-en-1-one The same procedure as in Example 46 (step 1) was carried out except that tert-butylpiperazine-1-carboxylate (17.3 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1). Steps 1 and 2) were carried out in the same manner to obtain the title compound (16.4 mg).

Example 51 N-(1-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H- Imidazole-5-carbonyl)azetidin-3-yl)-N-methacrylamide Except that tert-butyl N-(azetidin-3-yl)-N-methylcarbamate hydrochloride (23.7 mg) was used instead of 3-N-BOC- used in Example 46 (step 1). The title compound (19.9 mg) was obtained by carrying out the same method as in Example 46 (steps 1 and 2) except for the amino azetidine.

Example 52 N-((2R ^* ,3R ^* )-1-acrylyl-2-methylazetidin-3-yl)-2-(((5-(tert-butyl))-6-chloro -1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide except using cis-tert-butyl3-amino-2-methyl Except for the 3-N-BOC-aminoazetidine used in Example 46 (step 1), the rest were carried out as in Example 46 (steps 1 and 2). ), thereby obtaining the title compound (18.0 mg).

Example 53 N-(1-propenyl-4,4-difluoropyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl) Amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide In addition to using 1-(4-amino-3,3-difluoropyrrolidin-1-yl)prop-2-en-1-one trifluoroacetate (26.9 mg) obtained in Production Example 28, the 46 (step 1) except for 3-N-BOC-aminoazetidine, the same method as in Example 46 (step 1) was carried out to obtain the title compound (7.7 mg).

Example 54 (R)-N-(5-propenyl-5-azaspiro[2.4]heptan-7-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indol Azol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide In addition to using (R)-1-(7-amino-5-azaspiro[2.4]heptan-5-yl)prop-2-en-1-one trifluoroacetate (38.9) obtained in Production Example 29 mg) was substituted for 3-N-BOC-aminoazetidine used in Example 46 (step 1), and the same method as in Example 46 (step 1) was carried out to obtain the title compound (22.3 mg) .

Example 55 N-((3R,4R)-1-propenyl-4-methylpyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole- 3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide Instead of using 1-((3R,4R)-3-amino-4-methylpyrrolidin-1-yl)prop-2-en-1-one trifluoroacetate (37.3 mg) obtained in Production Example 30 The title compound (22.2 mg) was obtained by carrying out the same method as in Example 46 (step 1) except that 3-N-BOC-aminoazetidine was used in Example 46 (step 1).

Example 56 N-((3S,4R)-1-propenyl-4-hydroxypyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole-3) -(yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide Except that tert-butyl(3S,4R)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate (18.7 mg) was used instead of 3-N-BOC- used in Example 46 (step 1). The title compound (21.8 mg) was obtained by performing the same method as in Example 46 (steps 1 and 2) except for the amino azetidine.

Example 57 N-((3S,4R)-1-propenyl-4-fluoropyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole-3) -(yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide Except that tert-butyl(3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (18.9 mg) was used instead of the 3-N-BOC-amine used in Example 46 (step 1). Except for azetidine, the same method as in Example 46 (steps 1 and 2) was carried out to obtain the title compound (24.2 mg).

Example 58 N-((3R,4R)-1-propenyl-4-(hydroxymethyl)pyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H- Indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide Except that tert-butyl(3R,4R)-3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate (20.0 mg) was used instead of 3-N used in Example 46 (Step 1) Except for -BOC-aminoazetidine, the same method as in Example 46 (steps 1 and 2) was carried out to obtain the title compound (20.2 mg).

Example 59 N-(trans-1-propenyl-2-methylacetidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl) )Amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide Except that trans-tert-butyl 3-amino-2-methylazetidine-1-carboxylate (22.6 mg) was used instead of the 3-N-BOC-aminoacridine used in Example 46 (step 1). The title compound (16.2 mg) was obtained by carrying out the same method as in Example 46 (steps 1 and 2) except butidine.

Example 60 N-((3R,4S)-1-propenyl-4-methylpyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole- 3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide Except that tert-butyl(3R,4S)-3-amino-4-methylpyrrolidine-1-carboxylate (28.2 mg) was used instead of 3-N-BOC- used in Example 46 (step 1). The title compound (16.3 mg) was obtained by carrying out the same method as in Example 46 (steps 1 and 2) except for the amino azetidine.

Example 61 N-((3S,4R)-1-propenyl-4-methoxypyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole) -3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide Except that tert-butyl(3S,4R)-3-amino-4-methoxypyrrolidine-1-carboxylate (26.9 mg) was used instead of 3-N-BOC used in Example 46 (step 1). - Except for the amino azetidine, the same method as in Example 46 (steps 1 and 2) was carried out to obtain the title compound (20.7 mg).

Example 62 N-((3S,4S)-1-propenyl-4-hydroxypyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole-3) -(yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide Except that tert-butyl(3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate (18.7 mg) was used instead of the 3-N-BOC-amine used in Example 46 (step 1). Except for azetidine, the same method as in Example 46 (steps 1 and 2) was carried out to obtain the title compound (18.5 mg).

Example 63 N-((3S,4S)-1-propenyl-4-methoxypyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole) -3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide Except that tert-butyl(3S,4S)-3-amino-4-methoxypyrrolidine-1-carboxylate (20.0 mg) was used instead of 3-N-BOC used in Example 46 (step 1). -Amino azetidine, and using acrylic anhydride instead of acrylic chloride used in Example 46 (step 2), the same method as in Example 46 (steps 1 and 2) was carried out to obtain the title compound ( 19.3mg).

Example 64 N-((3S,4S)-1-propenyl-4-fluoropyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole-3) -(yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide Except that tert-butyl(3S,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (21.1 mg) was used instead of the 3-N-BOC-amine used in Example 46 (step 1). Except for azetidine, the same method as in Example 46 (steps 1 and 2) was carried out to obtain the title compound (6.1 mg).

Example 65 N-((3R,4R)-1-propenyl-4-(cyanomethyl)pyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H -Indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide was used except tert-butyl(3R,4R)- obtained in Production Example 31. 3-Amino-4-(cyanomethyl)pyrrolidine-1-carboxylate (20.9 mg) was substituted for the 3-N-BOC-aminoazetidine used in Example 46 (step 1). The same method as in Example 46 (steps 1 and 2) was carried out to obtain the title compound (12.9 mg).

Example 66 N-((3R,4R)-1-propenyl-4-(fluoromethyl)pyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H- Indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide was used except tert-butyl(3R,4R)-3 obtained in Production Example 32. -Amino-4-(fluoromethyl)pyrrolidine-1-carboxylate (17.9 mg) was substituted for 3-N-BOC-aminoazetidine used in Example 46 (step 1), and the rest were carried out The title compound (11.3 mg) was obtained in the same manner as in Example 46 (steps 1 and 2).

Example 67 N-((3R,4R)-1-propenyl-4-(methoxymethyl)pyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro- 1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide was used except for tert-butyl (3R, 4R) obtained in Production Example 33. -3-Amino-4-(methoxymethyl)pyrrolidine-1-carboxylate (16.0 mg) was substituted for 3-N-BOC-aminoazetidine used in Example 46 (Step 1) Except for this, the same method as in Example 46 (steps 1 and 2) was carried out to obtain the title compound (18.5 mg).

Example 68 N-((3R,4R)-1-propenyl-4-((dimethylamino)methyl)pyrrolidin-3-yl)-2-(((5-(tert-butyl)- 6-Chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide In addition to using tert-butyl(3R,4R)-3-amino-4-((dimethylamino)methyl)pyrrolidine-1-carboxylate (10.2 mg) obtained in Production Example 34, The title compound (7.9 mg) was obtained by carrying out the same method as in Example 46 (steps 1 and 2) except for 3-N-BOC-aminoazetidine used in Example 46 (step 1).

Example 69 N-((3R,4R)-1-propenyl-4-ethylpyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole- 3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide Except that tert-butyl(3R,4R)-3-amino-4-ethylpyrrolidine-1-carboxylate (8.6 mg) was used instead of 3-N-BOC- used in Example 46 (step 1). The title compound (5.2 mg) was obtained by carrying out the same method as in Example 46 (steps 1 and 2) except for the amino azetidine.

Example 70 N-((3S,4S)-1-propenyl-4-fluoropyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole-3) -(yl)amino)methyl)-4-(difluoromethyl)-1-methyl-1H-imidazole-5-carboxamide (Step 1) 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoro) obtained in Production Example 45 Methyl)-1-methyl-1H-imidazole-5-carboxylic acid (30mg), tert-butyl (3S,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (20mg) To the DMF (1.2 mL) solution, add N,N-diisopropylethylamine (20 μL) and HATU (39 mg), and stir at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction liquid. The organic layer was separated and washed with saturated brine. Dry with sodium sulfate, remove the solvent by distillation under reduced pressure, and perform column chromatography purification of the obtained residue (ethyl acetate:methanol) to obtain tert-butyl (3S,4S)-3-( 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1-methyl-1H- Imidazole-5-carboxamide)-4-fluoropyrrolidine-1-carboxylate (34.1 mg). (Step 2) For tert-butyl(3S,4S)-3-(2-(((5-(tert-butyl))-6-chloro-1H-indazol-3-yl) obtained in the above step 1 )Amino)methyl)-4-(difluoromethyl)-1-methyl-1H-imidazole-5-carboxamide)-4-fluoropyrrolidine-1-carboxylate (34.1 mg) was added Fluoroacetic acid (3.0 mL). After stirring at room temperature for 10 minutes, the reaction solution was concentrated. THF (2.0 mL) and N,N-diisopropylethylamine (54 μL) were added to the obtained residue, and then, a 1 M acrylic chloride acetonitrile solution (63 μL) was added. After stirring at room temperature for 10 minutes, water and ethyl acetate were added. The organic layer was separated and washed with saturated brine. The residue was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:methanol) to obtain the title compound (29.7 mg).

Example 71 N-((3R,4R)-1-propenyl-4-methylpyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole- 3-yl)amino)methyl)-4-(difluoromethyl)-1-methyl-1H-imidazole-5-carboxamide Except using 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl) obtained in Production Example 45 -1-Methyl-1H-imidazole-5-carboxylic acid (20 mg) substituted for 2-(((5-(tert-butyl)-6-chloro-1H-indazole) used in Example 46 (step 1) -3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxylic acid, and 1-((3R,4R)-3-amino obtained in Production Example 30 was used Proceed as in Example 46 except that -4-methylpyrrolidin-1-yl)prop-2-en-1-one trifluoroacetate (39.1 mg) was substituted for 3-N-BOC-aminoazetidine. (Step 1) The same method, whereby the title compound (20.4 mg) was obtained.

Example 72 (R)-N-(1-Acrylylpyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) Methyl)-4-fluoro-1-methyl-1H-imidazole-5-methamide (Step 1) To tert-butyl 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) obtained in Production Example 46 -Fluoro-1-methyl-1H-imidazole-5-carboxylate (19.4 mg) was added with trifluoroacetic acid (209 μL). After stirring at room temperature for 30 minutes, it was concentrated under reduced pressure to obtain 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Fluoro-1-methyl-1H-imidazole-5-carboxylic acid. (Step 2) In addition to using 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-fluoro- 1-Methyl-1H-imidazole-5-carboxylic acid substituted for 2-(((5-(tert-butyl)-6-chloro-1H-indazole-3-yl) used in Example 70 (step 1) )amino)methyl)-4-(difluoromethyl)-1-methyl-1H-imidazole-5-carboxylic acid, and use (R)-(+)-1-BOC-3-aminopyrrole The same method as in Example 70 (steps 1 and 2) was carried out except that tert-butyl (3S, 4S)-3-amino-4-fluoropyrrolidine-1-carboxylate was replaced with tert-butyl (3S, 4S)-3-fluoropyrrolidine-1-carboxylate. , thereby obtaining the title compound (10.2 mg).

Example 73 (R)-N-(1-Acrylylpyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) Methyl)-4-chloro-1-methyl-1H-imidazole-5-methamide Except that 4-chloro-1-methyl-1H-imidazole-5-carboxylic acid (78.6 mg) obtained in Production Example 13 was used instead of 4-cyano-1-methyl- used in Example 28 (step 1). 1H-imidazole-5-carboxylic acid, and (R)-(+)-1-BOC-3-aminopyrrolidine (119 mg) was used to replace 1-Boc-3-aminoazetidine, and the rest were carried out with The title compound (18.0 mg) was obtained by the same method as Example 28 (step 1-3).

Example 74 N-((3R,4R)-1-propenyl-4-methylpyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole- 3-yl)amino)methyl)-4-fluoro-1-methyl-1H-imidazole-5-carboxamide Instead of using 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-fluoro- 1-Methyl-1H-imidazole-5-carboxylic acid substituted for 2-(((5-(tert-butyl)-6-chloro-1H-indazole-3-yl) used in Example 70 (step 1) )amino)methyl)-4-(difluoromethyl)-1-methyl-1H-imidazole-5-carboxylic acid, and 1-((3R,4R)-3- obtained in Production Example 30 was used Amino-4-methylpyrrolidin-1-yl)prop-2-en-1-one trifluoroacetate (37.2 mg) substituted tert-butyl(3S,4S)-3-amino-4-fluoro Pyrrolidine-1-carboxylate, the same method as in Example 70 (step 1) was carried out, whereby the title compound (23 mg) was obtained.

Example 75 N-((3S,4S)-1-propenyl-4-fluoropyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole-3) -(yl)amino)methyl)-4-fluoro-1-methyl-1H-imidazole-5-carboxamide except that 2-(((5-(tert- Butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-fluoro-1-methyl-1H-imidazole-5-carboxylic acid substituted in Example 70 (Step 1) Used 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1-methyl- The title compound (12 mg) was obtained by performing the same method as in Example 70 (steps 1 and 2) except for 1H-imidazole-5-carboxylic acid.

Example 76 N-((3S,4S)-1-propenyl-4-fluoropyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole-3) -yl)amino)methyl)-4-chloro-1-methyl-1H-imidazole-5-carboxamide Except that 4-chloro-1-methyl-1H-imidazole-5-carboxylic acid (90.0 mg) obtained in Production Example 13 was used instead of 4-cyano-1-methyl- used in Example 28 (step 1). 1H-imidazole-5-carboxylic acid, and tert-butyl(3S,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (126 mg) was used instead of 1-Boc-3-aminoacridine The title compound (13.7 mg) was obtained by carrying out the same method as in Example 28 (step 1-3) except butidine.

Example 77 (R)-N-(1-Acrylylpyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) Methyl)-N,1-dimethyl-1H-imidazole-5-methamide Except that 1-methyl-1H-5-imidazolecarboxylic acid (252 mg) was used instead of 4-cyano-1-methyl-1H-imidazole-5-carboxylic acid used in Example 28 (step 1), and tert was used Proceed as in Example 28 (step 1) except -butyl(3R)-3-(methylamino)pyrrolidine-1-carboxylate (450 mg) instead of 1-Boc-3-aminoazetidine -3) The same method, whereby the title compound (49.1 mg) was obtained.

Example 78 N-((3R,4R)-1-propenyl-4-methylpyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole- 3-yl)amino)methyl)-4-chloro-1-methyl-1H-imidazole-5-carboxamide In addition to using 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-methyl obtained in Production Example 47 -1H-imidazole-5-carboxylic acid (35 mg) substituted for 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl) used in Example 70 (step 1) Amino)methyl)-4-(difluoromethyl)-1-methyl-1H-imidazole-5-carboxylic acid, and 1-((3R,4R)-3-amine obtained in Production Example 30 was used Tert-butyl(3S,4S)-3-amino-4-fluoropyrrole substituted with tert-4-methylpyrrolidin-1-yl)prop-2-en-1-one trifluoroacetate (37.2 mg) The title compound (22 mg) was obtained by carrying out the same method as in Example 70 (step 1) except for the ester of pyridine-1-carboxylate.

Example 79 (E)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1-isopropyl-4-methyl-N -(1-(4-(piperidin-1-yl)but-2-enyl)azetidin-3-yl)-1H-imidazole-5-methamide (Step 1) To tert-butyl 3-(2-(((5-(tert-butyl))-6-chloro-1H-indazol-3-yl)amino)methyl obtained in Production Example 48 )-1-isopropyl-4-methyl-1H-imidazole-5-carboxamide) azetidine-1-carboxylate (165 mg) was added trifluoroacetic acid (1.5 mL) and stirred at room temperature 30 minutes. The reaction liquid was concentrated, toluene was added to the obtained residue, and the concentration was repeated twice. Add DMF (1.5mL), 4-bromocrotonic acid (73.4mg), N,N-diisopropylethylamine (402μL), propylphosphonic anhydride (cyclic trimer, 50% ethyl acetate solution) (272 mg) and stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction liquid, and the organic layer was separated. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:methanol), thereby obtaining N-(1-(4-bromobut-2-enyl)acridine Butidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1-isopropyl-4- Methyl-1H-imidazole-5-carboxamide (57.9 mg). (Step 2) N-(1-(4-bromobut-2-enyl)azetidin-3-yl)-2-(((5-(tert-butyl)) obtained in the above-mentioned step 1 -6-Chloro-1H-indazol-3-yl)amino)methyl)-1-isopropyl-4-methyl-1H-imidazole-5-methamide (57.9 mg) in DMF (500 μL) Piperidine (17.7 mg), potassium carbonate (42.2 mg), and potassium iodide (17.1 mg) were added to the solution, and stirred at room temperature for 70 minutes. Water and ethyl acetate were added to the reaction liquid, and the organic layer was separated. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (basic silica gel, hexane: ethyl acetate), thereby obtaining the title compound (26 mg).

Example 80 (E)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-N-(1-(4-(dimethyl) Amino)but-2-enyl)azetidine-3-yl)-1,4-dimethyl-1H-imidazole-5-carboxamide For tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1 obtained in Production Example 49, Trifluoroacetic acid (1.5 mL) was added to 4-dimethyl-1H-imidazole-5-carboxamide) azetidine-1-carboxylate (12.9 mg) and stirred at room temperature for 15 minutes. The reaction liquid was concentrated, toluene was added to the obtained residue, and the concentration was repeated twice. Add dichloromethane (2.0 mL), N,N-diisopropylethylamine (83 μL), 1-hydroxybenzotriazole hydrate (6.0 mg), (E)-4-(dimethylamino ) But-2-enoic hydrochloride (14.0 mg), WSC hydrochloride (10.8 mg). Stir at room temperature for 1 hour, concentrate the reaction solution, add water and ethyl acetate, and separate the organic layer. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (basic silica gel, hexane:ethyl acetate), thereby obtaining the title compound (7.6 mg).

Example 81 (E)-N-(1-(but-2-enyl)azetidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole- 3-yl)amino)methyl)-1-isopropyl-4-methyl-1H-imidazole-5-carboxamide For tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1- obtained in Production Example 48 Trifluoroacetic acid (1.5 mL) was added to isopropyl-4-methyl-1H-imidazole-5-carboxamide) azetidine-1-carboxylate (165 mg) and stirred at room temperature for 30 minutes. The reaction liquid was concentrated, toluene was added to the obtained residue, and the concentration was repeated twice. THF (2.0 mL), N,N-diisopropylethylamine (130 μL), and crotonyl chloride (4.1 μL) were added, and stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:methanol), thereby obtaining the title compound (21.6 mg).

Example 82 N-(1-(but-2-enyl)azetidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl) Amino)methyl)-1-isopropyl-4-methyl-1H-imidazole-5-carboxamide For tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1- obtained in Production Example 48 Trifluoroacetic acid (1.5 mL) was added to isopropyl-4-methyl-1H-imidazole-5-carboxamide) azetidine-1-carboxylate (47.6 mg) and stirred at room temperature for 15 minutes. The reaction liquid was concentrated, toluene was added to the obtained residue, and the concentration was repeated twice. Add dichloromethane (2.0 mL), N,N-diisopropylethylamine (145 μL), 1-hydroxybenzotriazole hydrate (15.5 mg), 2-butynoic acid (12.0 mg), and WSC salt. salt (24.9mg). After stirring at room temperature for 6 hours, water and ethyl acetate were added, and the organic layer was separated. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (basic silica gel, hexane:ethyl acetate), thereby obtaining the title compound (16.6 mg).

Example 83 (Z)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-N-(1-(3-chloroacrylyl) )Azetidin-3-yl)-1-isopropyl-4-methyl-1H-imidazole-5-methamide The title compound (10.0 mg) was obtained in the same manner as in Example 82 except that CIS-3-chloroacrylic acid (14.8 mg) was used instead of 2-butynoic acid used in Example 82.

Example 84 (E)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-N-( 1-(4-(dimethylamino)but-2-enyl)azetidin-3-yl)-1-isopropyl-1H-imidazole-5-carboxamide Instead of using tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4 obtained in Production Example 50 -(Difluoromethyl)-1-isopropyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (29.9 mg) substituted for tert-butyl 3- used in Example 80 (2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-methyl The title compound (16.4 mg) was obtained by carrying out the same method as in Example 80 except for amide) azetidine-1-carboxylate.

Example 85 (E)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1-isopropyl-N-(1-( 4-Methoxybut-2-enyl)azetidin-3-yl)-4-methyl-1H-imidazole-5-methamide The same method as in Example 82 was carried out except that (E)-4-methoxybut-2-enoic acid (17.6 mg) was used instead of 2-butynoic acid used in Example 82 to obtain the title compound (1.4mg).

Example 86 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1-isopropyl-4-methyl-N-(1- (Vinylsulfonyl)azetidin-3-yl)-1H-imidazole-5-carboxamide The title compound (3.2 mg) was obtained in the same manner as in Example 81 except that ethylene sulfonyl chloride (3.64 μL) was used instead of crotonyl chloride used in Example 81.

Example 87 N-(1-propenyl azetidin-3-yl)-1-butyl-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine (methyl)methyl)-4-chloro-1H-imidazole-5-methamide (Step 1) To a solution of imidazole-4-carboxylic acid methyl ester (1.2g) in DMF (13mL), potassium carbonate (2.07g) and 1-iodobutane (1.60mL) were added, and the mixture was stirred at room temperature for 2 hours 30 point. The reaction solution was filtered and concentrated, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining 1-butyl-1H-imidazole-5-carboxylic acid methyl ester (695 mg ). (Step 2) Add 5N sodium hydroxide aqueous solution (3.0 mL) to the ethanol (6.0 mL) solution of 1-butyl-1H-imidazole-5-carboxylic acid methyl ester (390 mg) obtained in the above step 1, and mix in the chamber Stir at warm temperature for 1 hour. Water was added to the reaction solution, ethanol was distilled off, and 10% phosphoric acid aqueous solution was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The mixture was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1-butyl-1H-imidazole-5-carboxylic acid (125 mg). (Step 3) Add the DMF (3.0 mL) solution of 1-butyl-1H-imidazole-5-carboxylic acid (125 mg) and 1-Boc-3-aminoazetidine (200 mg) obtained in the above step 2. N,N-diisopropylethylamine (250 μL), HATU (300 mg). Stir at room temperature for 30 minutes, add water and ethyl acetate, and separate the organic layer. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(1-butyl-1H-imidazole-5) -Formamide) azetidine-1-carboxylate (186 mg). (Step 4) To tert-butyl 3-(1-butyl-1H-imidazole-5-carboxamide) azetidine-1-carboxylate (186 mg) obtained in the above step 3, THF (7.0 mL), 2,2,6,6-tetramethylpiperidine (500 μL) was cooled in a dry ice acetone bath, and butyllithium (1.55 M hexane solution, 2.23 mL) was added. While cooling in a dry ice acetone bath, the mixture was stirred for 1 hour and 20 minutes, DMF (500 μL) was added, and the mixture was stirred for another 1 hour. Water and 10% phosphoric acid aqueous solution were added to the reaction solution, and the temperature was raised to room temperature. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to column chromatography and purification (chloroform:ethanol), thereby obtaining tert-butyl 3-(1-butyl-2-formyl-1H-imidazole-5-formamide) azedine Ridine-1-carboxylate (200 mg). (Step 5) To tert-butyl 3-(1-butyl-2-carboxylic acid-1H-imidazole-5-formamide)azetidine-1-carboxylate obtained in the above-mentioned step 4 (191 mg ) in DMF (2.0 mL), add N-chlorosuccinimide (80 mg), and stir at 50°C for 2 hours and 40 minutes. Saturated sodium bicarbonate aqueous solution and sodium thiosulfate aqueous solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(1-butyl-4-chloro-2-formyl-1H-imidazole-5) -Formamide) azetidine-1-carboxylate (97.5 mg). (Step 6) In addition to using tert-butyl 3-(1-butyl-4-chloro-2-formyl-1H-imidazole-5-formamide)azetidine-1- obtained in the above step 5 Carboxylate (96 mg) substituted for tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide)azetidine-1-carboxylic acid used in Example 2 (step 4) Except for the ester, the same method as in Example 2 (steps 4 and 5) was carried out to obtain the title compound (61.6 mg).

Example 88 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1-(3,5-dimethoxybenzyl)-1H-imidazole-5-carboxamide (Step 1) To a suspension of imidazole-4-carboxylic acid methyl ester (500 mg) and triphenylphosphine (1.57 g) in THF (10 mL), 3,5-dimethoxybenzyl alcohol (804 mg) was added. DIAD (1.17 mL) was added slowly and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining crude methyl 1-(3,5-dimethoxybenzyl) -1H-imidazole-5-carboxylate. (Step 2) Add 4N sodium hydroxide to a solution of crude methyl 1-(3,5-dimethoxybenzyl)-1H-imidazole-5-carboxylate obtained in step 1 above in methanol (5.0 mL). Aqueous solution (2.97mL). After stirring at 100° C. for 40 minutes, the mixture was cooled to room temperature, and water and ethyl acetate were added to the reaction solution. The aqueous layer was separated and washed with ethyl acetate. 6N hydrochloric acid was added, and the precipitated solid was collected to obtain 1-(3,5-dimethoxybenzyl)-1H-imidazole-5-carboxylic acid (1.04g). (Step 3) Add 1-Boc-3-aminoazetidine to 1-(3,5-dimethoxybenzyl)-1H-imidazole-5-carboxylic acid (1.04g) obtained in the above step 2. (685mg), DMF (3.0mL), 1-hydroxybenzotriazole hydrate (601mg), N,N-diisopropylethylamine (2.0mL), WSC hydrochloride (1.53g). After stirring at room temperature for 2 hours, water and ethyl acetate were added. The organic layer was separated and washed with saturated brine. Dry with sodium sulfate, remove the solvent by distillation under reduced pressure, and subject the obtained residue to column chromatography purification (chloroform:methanol) to obtain tert-butyl 3-(1-(3,5-di Methoxybenzyl)-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (1.13 g). (Step 4) In addition to using tert-butyl 3-(1-(3,5-dimethoxybenzyl)-1H-imidazole-5-carboxamide)azetidine-1- obtained in the above Step 3 Carboxylic acid ester (1.13 g) substituted for tert-butyl 3-(4-cyano-1-methyl-1H-imidazole-5-carboxamide)azetidine-1 used in Example 28 (Step 2) - Except for the carboxylic acid ester, the same method as in Example 28 (steps 2 and 3) was carried out, whereby the title compound (31 mg) was obtained.

Example 89 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-isobutyl-1H-imidazole-5-methamide (Step 1) The same procedure as in Example 88 (Step 1) was carried out except that 2-methyl-1-propanol was used instead of 3,5-dimethoxybenzyl alcohol used in Example 88 (Step 1). 2) The same method, whereby 1-isobutyl-1H-imidazole-5-carboxylic acid (277 mg) was obtained. (Step 2) 1-isobutyl-1H-imidazole-5-carboxylic acid (277 mg) and 1-Boc-3-aminoazetidine (285 mg) obtained in the above step 1 were dissolved in dichloromethane (5.0 mL) ) solution, add 1-hydroxybenzotriazole hydrate (258 mg), N,N-diisopropylethylamine (840 μL), and WSC hydrochloride (473 mg). After stirring at room temperature for 1 hour, water and ethyl acetate were added. The organic layer was separated and washed with saturated brine. Dry with sodium sulfate, distill the solvent under reduced pressure, and perform column chromatography purification of the obtained residue (ethyl acetate:methanol) to obtain tert-butyl 3-(1-isobutyl- 1H-imidazole-5-carboxamide) azetidine-1-carboxylate (388 mg). (Step 3) In addition to using tert-butyl 3-(1-isobutyl-1H-imidazole-5-carboxylic acid ester) azetidine-1-carboxylate (388 mg) obtained in the above step 2, the substitution was carried out. Except for using tert-butyl 3-(1-butyl-1H-imidazole-5-carboxylic acid ester) azetidine-1-carboxylate in Example 87 (step 4), proceed with the same procedure as in Example 87 (step 4). 4-6) The same method was used to obtain the title compound (33.1 mg).

Example 90 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(2-methoxyethyl)-1H-imidazole-5-carboxamide The procedure was carried out as in Example 88 (Step 1-3), except that 2-methoxyethanol (227 mg) was used instead of 3,5-dimethoxybenzyl alcohol used in Example 88 (Step 1). The same method as in Example 87 (step 4-6) was carried out, whereby the title compound (27.8 mg) was obtained.

Example 91 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-(difluoromethyl)-1-(1-methylpyrrolidin-3-yl)-1H-imidazole-5-carboxamide (Step 1) p-Dimethyl 2-bromo-1H-imidazole-4,5-dicarboxylate (1.0g), triphenylphosphine (1.10g), 1-(tert-butoxycarbonyl)-3 - A solution of pyrrolidinol (800 mg) in THF (6.0 mL) was added with DIAD (823 μL) and stirred at 40°C for 1 hour. Water was added to the reaction liquid, the reaction liquid was concentrated under reduced pressure, and the obtained residue was subjected to column chromatography purification (hexane: ethyl acetate) to obtain crude dimethyl 2-bromo-1-( 1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-imidazole-4,5-dicarboxylate (1.88 g). (Step 2) Use the crude dimethyl 2-bromo-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-imidazole-4,5-dicarboxylic acid obtained in the above step 1. A solution of the acid ester (1.88 g) in THF (16 mL) was cooled in a dry ice acetone bath, and diisobutylaluminum hydride (1M toluene solution) (8.9 mL) was added and stirred for 7 hours while cooling in a dry ice acetone bath. Rochelle aqueous solution was added to the reaction solution, the temperature was raised to room temperature, and the mixture was stirred overnight. It was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl 2-bromo-1-(1-(tert-butoxy) Carbonyl)pyrrolidin-3-yl)-4-methanoyl-1H-imidazole-5-carboxylate (1.24 g). (Step 3) To methyl 2-bromo-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-methanoyl-1H-imidazole-5- obtained in the above step 2 To a solution of the carboxylic acid ester (1.24 g) in dichloromethane (15 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (2.3 mL) and stirred at room temperature for 2 hours. Cool in a water bath and slowly add water. The reaction solution was extracted with dichloromethane and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl 2-bromo-1-(1-(tert-butoxy) Carbonyl)pyrrolidin-3-yl)-4-(difluoromethyl)-1H-imidazole-5-carboxylate (902 mg). (Step 4) Methyl 2-bromo-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(difluoromethyl)-1H-imidazole obtained in the above step 3 A solution of -5-carboxylate (902 mg) in THF (13.5 mL) was cooled under a dry ice acetone bath and isopropylmagnesium chloride (2 MTHF solution) (2.52 mL) was added over 5 minutes. After the reaction solution was stirred for 45 minutes while cooling, DMF (827 μL) was added. After leaving the dry ice acetone bath for 20 minutes, 2N hydrochloric acid (2.5 mL) and saturated aqueous ammonium chloride solution (30 mL) were added to the reaction solution at 0°C. The reaction solution was washed with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl 1-(1-(tert-butoxycarbonyl)pyrrolidine -3-yl)-4-(difluoromethyl)-2-carboxyl-1H-imidazole-5-carboxylate (415 mg). (Step 5) To methyl 1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(difluoromethyl)-2-methanoyl-1H obtained in the above Step 4 - Imidazole-5-carboxylate (47.7 mg), 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (30 mg) obtained in Production Example 1 in dichloromethane (4.0 mL ) solution, add trifluoroacetic acid (19.6 μL) and sodium triacetoxyborohydride (52.0 mg). After stirring at room temperature for 2 hours, a sodium bicarbonate aqueous solution was added to the reaction liquid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:methanol), thereby obtaining methyl 1-(1-(tert-butoxycarbonyl)pyrrolidine- 3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1H- Imidazole-5-carboxylate (68 mg). (Step 6) To the methyl 1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-(((5-(tert-butyl)-6- To a solution of chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1H-imidazole-5-carboxylate (68 mg) in methanol (3 mL) was added 1N sodium hydroxide aqueous solution (1 mL) and stirred at room temperature for 30 minutes. The reaction solution was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain crude 1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro- 1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1H-imidazole-5-carboxylic acid (68 mg). (Step 7) Add the crude 1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro) obtained in the above Step 6 -1H-indazole-3-yl)amino)methyl)-4-(difluoromethyl)-1H-imidazole-5-carboxylic acid (40 mg), 1-(3-amine obtained in Production Example 27 Azetidin-1-yl)prop-2-en-1-one hydrochloride (13.8 mg) and DMF (1.0 mL) were further added to N,N-diisopropylethylamine (31 μL) and HATU (38 mg) and stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:methanol), thereby obtaining tert-butyl 3-(5-((1-propenyl azedine Dyn-3-yl)aminoformyl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(di Fluoromethyl)-1H-indazol-1-yl)pyrrolidine-1-carboxylate (32.2 mg). (Step 8) To tert-butyl 3-(5-((1-acrylyl azedine-3-yl)aminomethyl)-2-(((5-(tert -Butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1H-indazol-1-yl)pyrrolidine-1-carboxylic acid Trifluoroacetic acid (1 mL) was added to the ester (32.2 mg), and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated and purified by reverse phase separation HPLC (water: acetonitrile (0.1% formic acid)) to obtain N-(1-propenyl azedine-3-yl)-2-(((5-(tert -Butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1-(pyrrolidin-3-yl)-1H-imidazole-5 - Methamide formate (16.1 mg). (Step 9) Add N-(1-acrylyl azetidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole) obtained in step 8 above) -3-yl)amino)methyl)-4-(difluoromethyl)-1-(pyrrolidin-3-yl)-1H-imidazole-5-carboxylic acid salt (5.0 mg) in DMF (300 μL), acetic acid (30 μL), formaldehyde solution (37%) (10 μL), and then sodium triacetyloxyborohydride (6.9 mg) was added. DMSO (1.0 mL) was added to the reaction solution, and the mixture was purified by reverse phase separation HPLC (water: acetonitrile (0.1% formic acid)). After concentration, 5N sodium hydroxide aqueous solution (1.5 mL) was added, extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.35 mg).

Example 92 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-(Difluoromethyl)-1-(1-ethylpyrrolidin-3-yl)-1H-imidazole-5-carboxamide The title compound (3.12 mg) was obtained in the same manner as in Example 91 (step 9) except that acetaldehyde (20 mg) was used instead of the formaldehyde solution used in Example 91 (step 9).

Example 93 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-(Difluoromethyl)-1-(1-isopropylpyrrolidin-3-yl)-1H-imidazole-5-carboxylic acid salt Except using acetone (20 mg) instead of the formaldehyde solution used in Example 91 (step 9), the same method as in Example 91 (step 9) was carried out, using reverse phase separation HPLC (water: acetonitrile (0.1% formic acid) )) After purification, the solvent was concentrated to obtain the title compound (8.33 mg).

Example 94 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(pyridin-2-yl)-1H-imidazole-5-carboxamide (Step 1) Methyl 4-chloro-1H-imidazole-5-carboxylate (320 mg), 2-bromopyridine (650 mg), potassium carbonate (420 mg), and copper iodide (I) obtained in Production Example 12 (380 mg) of a suspension in 1,4-dioxane (7.0 mL) was added trans-N,N'-dimethylcyclohexane-1,2-diamine (320 μL) and stirred at 100°C overnight . The reaction solution was cooled to room temperature, and concentrated ammonia water and ethyl acetate were added. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl 4-chloro-1-(pyridin-2-yl)-1H. - Imidazole-5-carboxylate (115 mg). (Step 2) Instead of using methyl 4-chloro-1-(pyridin-2-yl)-1H-imidazole-5-carboxylate (115 mg) obtained in the above Step 1, it was used in Production Example 38 (Step 2). Except for methyl 4-chloro-1-isopropyl-1H-imidazole-5-carboxylate, the same method as in Production Example 38 (step 2-4) was carried out to obtain tert-butyl 3- (4-Chloro-2-formamide-1-(pyridin-2-yl)-1H-imidazole-5-formamide)azetidine-1-carboxylate (48.7 mg). (Step 3) In addition to using tert-butyl 3-(4-chloro-2-formyl-1-(pyridin-2-yl)-1H-imidazole-5-formamide) acridine obtained in the above step 2 Butidine-1-carboxylate (48.7 mg) replaced tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide) azedine used in Example 2 (step 4) The title compound (11.4 mg) was obtained by carrying out the same method as in Example 2 (steps 4 and 5) except for the ester of pyridine-1-carboxylate.

Example 95 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-(Difluoromethyl)-1-((1-isopropylpyrrolidin-2-yl)methyl)-1H-imidazole-5-carboxamide In addition to using N-(tert-butoxycarbonyl)-DL-prolinol instead of 1-(tert-butoxycarbonyl)-3-pyrrolidinol used in Example 91 (step 1), and using acetone ( Except that the formaldehyde solution used in Example 91 (step 9) was replaced with 20 mg), the same method as in Example 91 (step 1-9) was carried out to obtain the title compound (3.5 mg).

Example 96 1-(1-acetylpyrrolidin-3-yl)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro -1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1H-imidazole-5-carboxamide For N-(1-acrylyl azetidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole) obtained in Example 91 (Step 8) Pyridine of -3-yl)amino)methyl)-4-(difluoromethyl)-1-(pyrrolidin-3-yl)-1H-imidazole-5-carboxylic acid salt (18.0 mg) (40 μL) acetic anhydride (40 μL) was added to the solution and stirred at room temperature for 15 min. Methanol (2 mL) and concentrated ammonia water (2 mL) were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and purified by reverse phase separation HPLC (water: acetonitrile (0.1% formic acid)) to obtain the title compound (1.08 mg).

Example 97 (S)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-methamide (Step 1) Methyl 4-chloro-1H-imidazole-5-carboxylate (700 mg), triphenylphosphine (1.5 g), (R)-(-)-3-hydroxyl obtained in Production Example 12 To a solution of tetrahydrofuran (500 mg) in THF (12 mL) was added DIAD (1.15 mL) and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl (S)-4-chloro-1-(tetrahydrofuran-3- (634 mg)-1H-imidazole-5-carboxylate. (Step 2) A solution of methyl (S)-4-chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-carboxylate (634 mg) obtained in the above step 1 in THF (12.0 mL) DMF (800 μL) was added, and 2,2,6,6-tetramethylpiperidinylmagnesium chloride and lithium chloride complex (1MTHF/toluene solution, 11 mL) were added at -10°C. After stirring for 20 minutes, water, 10% phosphoric acid aqueous solution, and ethyl acetate were added, and the temperature was raised to room temperature. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl (S)-4-chloro-2-formyl-1 -(Tetrahydrofuran-3-yl)-1H-imidazole-5-carboxylate (266 mg). (Step 3) To methyl (S)-4-chloro-2-methanoyl-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-carboxylate (266 mg) obtained in the above step 2, To a solution of 5-(tert-butyl)-6-chloro-1H-indazol-3-amine (180 mg) obtained in Production Example 1 in dichloromethane (4.0 mL), trifluoroacetic acid (70 μL) and triethyl were added. Sodium acylborohydride (142 mg) and stirred at room temperature for 30 minutes. A sodium bicarbonate aqueous solution was added to the reaction liquid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl (S)-2-(((5-(tert-butan) (yl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-carboxylate (245 mg). (Step 4) (S)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4 obtained in the above step 3 -To a solution of chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-carboxylate (56 mg) in ethanol (1.2 mL), 5N aqueous sodium hydroxide solution (600 μL) was added, and stirred at room temperature for 30 minutes. . A 10% phosphoric acid aqueous solution was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue were added 1-(3-aminoazetidin-1-yl)prop-2-en-1-one hydrochloride (22 mg) and DMF (4 mL) obtained in Production Example 27, and N was further added , N-diisopropylethylamine (70μL), HATU (60mg). After stirring at room temperature overnight, 10% aqueous phosphoric acid solution and ethyl acetate were added. The organic layer was separated and washed with saturated brine. The mixture was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:ethanol) to obtain the title compound (26.1 mg).

Example 98 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(cyclopent-3-en-1-yl)-1H-imidazole-5-carboxamide (Step 1) Methyl 4-chloro-1H-imidazole-5-carboxylate (340 mg), triphenylphosphine (750 mg), and 3-cyclopenten-1-ol (240 mg) obtained in Production Example 12 DIAD (600 μL) was added to the solution in THF (12 mL) and stirred at room temperature for 30 min. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining crude methyl 4-chloro-1-(cyclopent-3-ene- 1-yl)-1H-imidazole-5-carboxylate (686 mg). (Step 2) Add ethanol (6.0 mL) to the crude methyl 4-chloro-1-(cyclopent-3-en-1-yl)-1H-imidazole-5-carboxylate (686 mg) obtained in the above step 1. ) solution was added 5N aqueous sodium hydroxide solution (4.0 mL), and stirred at room temperature for 20 minutes. Water was added to the reaction solution, ethanol was distilled off under reduced pressure, ethyl acetate was added, and the aqueous layer was separated. A 10% phosphoric acid aqueous solution was added to the obtained aqueous layer, extracted with ethyl acetate, and the organic layer was washed with saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. A solution of 1-Boc-3-aminoazetidine (500 mg) in DMF (5.0 mL), N,N-diisopropylethylamine (1.00 mL), and HATU (890 mg) was added to the obtained residue, and stirred 30 minutes. Ethyl acetate, water, and 10% phosphoric acid aqueous solution were added to the reaction solution to separate the layers, and the organic layer was washed with water and saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography purification (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(4-chloro-1-(cyclopent-3-en-1-yl)-1H -Imidazole-5-carboxamide) azetidine-1-carboxylate (550 mg). (Step 3) Use tert-butyl 3-(4-chloro-1-(cyclopent-3-en-1-yl)-1H-imidazole-5-methamide) azetidine obtained in the above step 2. -A mixture of 1-carboxylate (550 mg), THF (10.0 mL), and 2,2,6,6-tetramethylpiperidine (1.50 mL) was cooled in a dry ice acetone bath, and butyllithium ( 1.55M hexane solution, 5.80mL). While cooling in a dry ice acetone bath, the mixture was stirred for 2 hours, DMF (1.00 mL) was added, and the mixture was further stirred for 30 minutes. Add water and 10% phosphoric acid aqueous solution, and heat to room temperature. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to column chromatography purification (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(4-chloro-1-(cyclopent-3-en-1-yl)-2 -Formamide-1H-imidazole-5-formamide)azetidine-1-carboxylate (539 mg). (Step 4) To tert-butyl 3-(4-chloro-1-(cyclopent-3-en-1-yl)-2-methanoyl-1H-imidazole-5-methyl obtained in the above step 3) amide) azetidine-1-carboxylate (100 mg), 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (45 mg) obtained in Production Example 1 in dichloromethane (3.0 mL) trifluoroacetic acid (30 μL) and sodium triacetyloxyborohydride (120 mg) were added to the solution, and stirred at room temperature for 20 minutes. An aqueous sodium bicarbonate solution was added to the reaction liquid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining tert-butyl 3-(2-(((5-(tert- Butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(cyclopent-3-en-1-yl)-1H-imidazole-5-methyl amide) azetidine-1-carboxylate (80 mg). (Step 5) To tert-butyl 3-(2-(((5-(tert-butyl))-6-chloro-1H-indazol-3-yl)amino)methyl obtained in the above step 4 )-4-Chloro-1-(cyclopent-3-en-1-yl)-1H-imidazole-5-methamide)azetidine-1-carboxylate (80 mg) was added trifluoroacetic acid (1.00 mL ) and stir. The reaction solution was concentrated, and THF (3.0 mL) and N,N-diisopropylethylamine (300 μL) were added. Add 1 M solution of acrylic chloride in acetonitrile (130 μL) and stir at room temperature for 10 minutes. An aqueous sodium bicarbonate solution was added to the reaction liquid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform:ethanol) to obtain the title compound (52.8 mg).

Example 99 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-((3,4-dihydroxycyclopentyl)-1H-imidazole-5-methamide (Step 1) To tert-butyl 3-(4-chloro-1-(cyclopent-3-en-1-yl)-2-formyl-1H-imidazole obtained in Example 98 (Step 3) -5-Formamide) azetidine-1-carboxylate (110 mg) was added with acetone (3.0 mL), water (300 μL), 4-methylmorpholine N-oxide (70 mg), and 1% osmium tetroxide Aqueous solution (100 μL). After stirring at room temperature overnight, saturated sodium bicarbonate aqueous solution and sodium bisulfite were added to the reaction liquid. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to column chromatography and purification (chloroform:ethanol), thereby obtaining tert-butyl 3-(4-chloro-1-(3,4-dihydroxycyclopentyl)-2-formyl) -1H-imidazole-5-methamide)azetidine-1-carboxylate (111 mg). (Step 2) In addition to using tert-butyl 3-(4-chloro-1-(3,4-dihydroxycyclopentyl)-2-formyl-1H-imidazole-5-methyl obtained in step 1 above) Amido)azetidine-1-carboxylate (111 mg) was substituted for tert-butyl 3-(4-chloro-1-(cyclopent-3-en-1-yl) used in Example 98 (Step 4) )-2-formyl-1H-imidazole-5-formamide) azetidine-1-carboxylate, the same method as in Example 98 (steps 4, 5) was carried out to obtain the title compound (20.9 mg).

Example 100 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(2,2-difluoroethyl)-1H-imidazole-5-carboxamide The same method as in Example 98 (step 1-5) was carried out except that 2,2-difluoroethanol was used instead of 3-cyclopenten-1-ol used in Example 98 (step 1), whereby The title compound (72 mg) was obtained.

Example 101 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(tetrahydro-2H-piran-4-yl)-1H-imidazole-5-methamide Except that tetrahydro-4H-piran-4-ol is used instead of 3-cyclopenten-1-ol used in Example 98 (step 1), the same procedure as in Example 98 (step 1-5) is carried out. method, whereby the title compound (25.3 mg) was obtained.

Example 102 (R)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-methamide Except that (S)-(+)-3-hydroxytetrahydrofuran is used to replace 3-cyclopenten-1-ol used in Example 98 (step 1), the remaining procedures are the same as in Example 98 (step 1-5). method, thereby obtaining the title compound (54.1 mg).

Example 103 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(1-methylpiperidin-4-yl)-1H-imidazole-5-carboxamide (Step 1) Except for using tert-butyl 4-hydroxypiperidine-1-carboxylate to replace (R)-(-)-3-hydroxytetrahydrofuran used in Example 97 (Step 1), the rest were carried out with The same method as in Example 97 (step 1) was used to obtain tert-butyl 4-(4-chloro-5-methoxycarbonyl-imidazol-1-yl)piperidine-1-carboxylate (661 mg). (Step 2) Methanol (10 mL) to tert-butyl 4-(4-chloro-5-methoxycarbonyl-imidazol-1-yl)piperidine-1-carboxylate (661 mg) obtained in step 1 above ) solution, add 5N aqueous sodium hydroxide solution (5 mL), and stir at 40°C for 30 minutes. 5N hydrochloric acid was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1-(1-tert-butoxycarbonyl-4-piperidyl)-4-chloro-1H-indazole-5-carboxylic acid (514 mg). (Step 3) DMF (8 mL) of 1-(1-tert-butoxycarbonyl-4-piperidinyl)-4-chloro-1H-indazole-5-carboxylic acid (400 mg) obtained in the above Step 2 ) solution, add ethanol (1 mL), N,N-diisopropylethylamine (619 μL), and HATU (692 mg), and stir at 45°C for 50 minutes. Ethyl acetate and water were added to the reaction solution and the layers were separated, and the organic layer was washed with saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography purification (hexane/ethyl acetate) to obtain tert-butyl 4-(4-chloro-5-ethoxycarbonyl-imidazol-1-yl)piperidine- 1-Carboxylic acid ester (350 mg). (Step 4) THF (5 mL) of tert-butyl 4-(4-chloro-5-ethoxycarbonyl-imidazol-1-yl)piperidine-1-carboxylate (350 mg) obtained in the above Step 3 ) solution, DMF (485 μL) was added, and 2,2,6,6-tetramethylpiperidinylmagnesium chloride and lithium chloride complex (1MTHF/toluene solution, 6.12 mL) were added at -8°C. After stirring for 45 minutes, water, 5N hydrochloric acid, and ethyl acetate were added, and the temperature was raised to room temperature. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane/ethyl acetate), thereby obtaining tert-butyl 4-(4-chloro-5-ethoxycarbonyl) -2-Methodyl-imidazol-1-yl)piperidine-1-carboxylate (353 mg). (Step 5) tert-butyl 4-(4-chloro-5-ethoxycarbonyl-2-formyl-imidazol-1-yl)piperidine-1-carboxylate ( 240 mg) and a THF (2.5 mL) solution of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (146 mg) obtained in Production Example 1 was added with trifluoroacetic acid (50.0 μL), trifluoroacetic acid (50.0 μL), and trifluoroacetic acid (50.0 μL). Sodium acetylborohydride (270 mg) and stir at room temperature. Water was added to the reaction liquid, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane/ethyl acetate), thereby obtaining tert-butyl 4-(2-((5-tert-butyl (6-Chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-5-ethoxycarbonyl-imidazol-1-yl)piperidine-1-carboxylate (230 mg) . (Step 6) To tert-butyl 4-(2-(((5-tert-butyl-6-chloro-1H-indazol-3-yl)amino)methyl)- obtained in the above step 5 To a solution of 4-chloro-5-ethoxycarbonyl-imidazol-1-yl)piperidine-1-carboxylate (207 mg) in methanol (10 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and stirred at 40°C 3.5 hours. 2.5N hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. To the obtained residue were added 1-(3-aminoazetidin-1-yl)prop-2-en-1-one hydrochloride (73.7 mg) and DMF (4.14 mL) obtained in Production Example 27, and further , add N,N-diisopropylethylamine (178 μL) and HATU (199 mg). After stirring at room temperature for 30 minutes, water and ethyl acetate were added. The organic layer was separated and washed with 0.5N sodium hydroxide aqueous solution, water, 0.5N hydrochloric acid and saturated brine. Dry with sodium sulfate, concentrate the solvent under reduced pressure, and perform column chromatography purification of the obtained residue (ethyl acetate:methanol) to obtain tert-butyl 4-(2-(((5- tert-butyl-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-5-((1-prop-2-enyl azedine-3-yl) Carbonyl)imidazol-1-yl)piperidine-1-carboxylate (166 mg). (Step 7) To tert-butyl 4-(2-(((5-tert-butyl-6-chloro-1H-indazol-3-yl)amino)methyl)- obtained in the above step 6 A solution of 4-chloro-5-((1-prop-2-enyl azetidin-3-yl)carbonyl)imidazol-1-yl)piperidine-1-carboxylate (166 mg) in pyridine (1 mL) Acetic anhydride (1 mL) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate/methanol), thereby obtaining tert-butyl 4-(2-(((1-ethyl- 5-tert-butyl-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-5-((1-prop-2-enylazetidine-3- yl)carbonyl)imidazol-1-yl)piperidine-1-carboxylate (105 mg). (Step 8) To tert-butyl 4-(2-(((1-acetyl-5-tert-butyl-6-chloro-1H-indazol-3-yl)amine obtained in step 7 above) (methyl)methyl)-4-chloro-5-((1-prop-2-enyl azedine-3-yl)carbonyl)imidazol-1-yl)piperidine-1-carboxylate (105 mg) Add trifluoroacetic acid and stir at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. After concentration under reduced pressure, heptane was added and concentrated to obtain crude 2-(((1-acetyl-5-tert-butyl-6 -Chloro-indazol-3-yl)amino)methyl)-4-chloro-1-(4-piperidinyl)-N-(1-prop-2-enyl azedine-3-yl) ) imidazole-5-carboxamide trifluoroacetate (117 mg). (Step 9) 2-(((1-acetyl-5-tert-butyl-6-chloro-indazol-3-yl)amino)methyl)-4-chloro obtained in the above step 8 -Acetic acid was added to a methanol solution of 1-(4-piperidyl)-N-(1-prop-2-enolidenebutin-3-yl)imidazole-5-formamide trifluoroacetate (20 mg) Potassium (10 mg), formaldehyde solution (37%) (10 μL), and then sodium triacetyloxyborohydride (20 mg) was added. After stirring at room temperature for 30 minutes, water and ethyl acetate were added and separated, and the organic layer was separated and washed with 0.5N sodium hydroxide aqueous solution and saturated brine. The mixture was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. Methanol (2 mL) and 1N sodium hydroxide aqueous solution (29 μL) were added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction solution, and the mixture was washed with saturated brine. The mixture was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (12 mg).

Example 104 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(tetrahydro-2H-piran-3-yl)-1H-imidazole-5-methamide Except that tetrahydro-2H-piran-3-ol was used instead of 3-cyclopenten-1-ol used in Example 98 (step 1), the same procedures were carried out as in Example 98 (step 1-5). method, whereby the title compound (18.5 mg) was obtained.

Example 105 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-cyclopentyl-1H-imidazole-5-methamide The same method as in Example 98 (Step 1-5) was carried out except that cyclopentanol was used instead of 3-cyclopenten-1-ol used in Example 98 (Step 1), thereby obtaining the title compound ( 100mg).

Example 106 tert-butyl 3-(5-((1-propenyl azetidin-3-yl)aminomethanoyl)-2-(((5-(tert-butyl)-6-chloro-1H- Indazol-3-yl)amino)methyl)-4-chloro-1H-imidazol-1-yl)azetidine-1-carboxylate (Step 1) Methyl 4-chloro-1H-imidazole-5-carboxylate (1.0g), triphenylphosphine (3.27g), tert-butyl 3-hydroxyazetidine obtained in Production Example 12 -To a solution of 1-carboxylate (1.29g) in THF (1.5mL) and toluene (6.0mL), N,N-diisopropylethylamine (1.41mL) and azodicarboxylic acid bis(2-methyl) were added. oxyethyl) (2.92g) and stirred at 100°C for 1 hour. The reaction solution was cooled to room temperature, water and ethyl acetate were added, and the organic layer was separated. Wash with saturated brine, dry with sodium sulfate, and evaporate the solvent under reduced pressure. The obtained residue was subjected to column chromatography purification (hexane: ethyl acetate), thereby obtaining methyl 1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-4-chloro -1H-imidazole-5-carboxylate (1.30g). (Step 2) In addition to using the methyl 1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-4-chloro-1H-imidazole-5-carboxylate obtained in the above step 1 Except for the methyl (S)-4-chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-carboxylate used in Example 97 (step 2), the rest were carried out as in Example 97 (step 2). 2-4) The same method was used to obtain the title compound (88 mg).

Example 107 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(1-isopropylazetidin-3-yl)-1H-imidazole-5-carboxamide (step 1) versus tert-butyl obtained in Example 106 (step 2) 3-(5-((1-propenyl azetidin-3-yl)aminomethyl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole-3) To a solution of -(yl)amino)methyl)-4-chloro-1H-imidazol-1-yl)azetidine-1-carboxylate (88 mg) in pyridine (1.0 mL) was added acetic anhydride (1.0 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (chloroform:ethanol), thereby obtaining tert-butyl 3-(2-(( (1-acetyl-5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-5-((1-acrylyl azetidine-3 -(yl)carbamocarbonyl)-4-chloro-1H-imidazol-1-yl)azetidine-1-carboxylate (23 mg). (Step 2) To the tert-butyl 3-(2-(((1-acetyl-5-(tert-butyl))-6-chloro-1H-indazol-3-yl obtained in the above-mentioned step 1) )amino)methyl)-5-((1-acrylyl azetidine-3-yl)aminomethanoyl)-4-chloro-1H-imidazol-1-yl)azetidine-1-carboxy Trifluoroacetic acid (1 mL.) was added to the acid ester (23 mg), and the mixture was stirred and then concentrated. To the obtained residue were added THF (0.7 mL), acetone (5.5 μL), acetic acid (70 μL), and further, borane-2-methylpyridine complex (3 mg) was added. After stirring at room temperature for 40 minutes, 2N aqueous sodium hydroxide solution (0.7 mL) and methanol (0.3 mL) were added, and the mixture was stirred for 20 minutes. 5N hydrochloric acid (0.2 mL) was added, and extraction was performed with ethyl acetate. The organic layer was separated and washed with saturated brine. The residue was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:ethanol) to obtain the title compound (2.2 mg).

Example 108 1-(1-acetyl azedine-3-yl)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6- Chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1H-imidazole-5-carboxamide For tert-butyl 3-(5-((1-acrylyl azetidin-3-yl)aminomethanoyl)-2-((5-(tert) obtained in Example 106 (step 2) -Butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1H-imidazol-1-yl)azetidine-1-carboxylate (30 mg) added Trifluoroacetic acid (1.0 mL) was stirred and concentrated, and THF (1.0 mL), N,N-diisopropylethylamine (56 μL), and acetic anhydride (5 μL) were added to the obtained residue. After stirring at room temperature for 30 minutes, saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution. The organic layer was separated and washed with saturated brine. The mixture was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:ethanol) to obtain the title compound (4.5 mg).

Example 109 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-cyclohexyl-1H-imidazole-5-methamide The title compound ( 20.5 mg).

Example 110 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(cyclopentylmethyl)-1H-imidazole-5-methamide Except that cyclopentylmethanol is used to replace (R)-(-)-3-hydroxytetrahydrofuran used in Example 97 (step 1), the same method as in Example 97 (steps 1-4) is carried out, whereby The title compound (140 mg) was obtained.

Example 111 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-((1S,2S,5R)-2-isopropyl-5-methylcyclohexyl)-1H-imidazole-5-methamide Except using (-)-menthol instead of 3-cyclopenten-1-ol used in Example 98 (step 1), the same method as in Example 98 (step 1-5) was carried out, thereby obtaining Title compound (10.7 mg).

Example 112 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(4-methoxycyclohexyl)-1H-imidazole-5-carboxamide Except that 4-methoxycyclohexanol is used to replace (R)-(-)-3-hydroxytetrahydrofuran used in Example 97 (step 1), the same procedures as in Example 97 (steps 1-4) are carried out. method, whereby the title compound (140 mg) was obtained.

Example 113 (R)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-1H-imidazole-5-methamide (Step 1) Methyl (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-(((5-(tert-butyl)) obtained in Production Example 51 )-6-Chloro-1H-indazole-3-yl)amino)methyl)-4-chloro-1H-imidazole-5-carboxylate (437 mg) was added trifluoroacetic acid (3.0 mL) and incubated in the chamber After stirring at room temperature for 5 minutes, the reaction solution was concentrated. Methanol was added to the obtained residue, and the operation of concentrating under reduced pressure was repeated twice. Potassium acetate (400 mg), difluoroacetaldehyde hemiethyl alcohol (170 μL), and a methanol solution of 0.3 M sodium cyanoborohydride-1/2 zinc chloride (5.15 mL) were added to the obtained residue, and the mixture was stirred at room temperature. all night. The reaction solution was concentrated, and saturated aqueous sodium bicarbonate solution and ethyl acetate were added. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform:ethanol), thereby obtaining methyl (R)-2-(((5-(tert-butyl)- 6-Chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-1H-imidazole -5-carboxylate (261 mg). (Step 2) To the methyl (R)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) obtained in the above step 1 -A solution of 4-chloro-1-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-1H-imidazole-5-carboxylate (261 mg) in ethanol (3.0 mL) was added with 5N hydrogen Aqueous sodium oxide solution (1.00 mL). After stirring at room temperature for 30 minutes, 6N hydrochloric acid (820 μL) was added. THF was added to the reaction solution, the precipitated solid was filtered off, and the solid was washed with 2-propanol. The filtrate was concentrated under reduced pressure, and DMF (3.0 mL) and 1-(3-aminoazetidin-1-yl)prop-2-en-1-one salt obtained in Production Example 27 were added to the obtained residue. salt (120mg), 1-hydroxybenzotriazole hydrate (100mg), N,N-diisopropylethylamine (420μL), WSC hydrochloride (300mg), and stir at room temperature overnight . To the reaction solution were added saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform:ethanol) to obtain the title compound (241 mg).

Example 114 (R)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(1-isopropylpyrrolidin-3-yl)-1H-imidazole-5-methamide (Step 1) Methyl (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-(((5-(tert-butyl)) obtained in Production Example 51 )-6-Chloro-1H-indazole-3-yl)amino)methyl)-4-chloro-1H-imidazole-5-carboxylate (300 mg) was added trifluoroacetic acid (1.0 mL) and incubated in the chamber After stirring at room temperature for 15 minutes, the reaction solution was concentrated. Dichloromethane (5.0 mL), ethanol (0.5 mL), acetone (250 μL), and potassium acetate (150 mg) were added to the obtained residue. Next, sodium triacetoxyborohydride (350 mg) was added. Stir at room temperature for 2 hours. Sodium triacetylborohydride (100 mg) was added to the reaction liquid, and the mixture was stirred at room temperature for 1 hour. To the reaction solution were added saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography purification (basic silica gel: hexane: ethyl acetate), thereby obtaining methyl (R)-2-(((5-(tert-butyl)-6-chloro -1H-indazol-3-yl)amino)methyl)-4-chloro-1-(1-isopropylpyrrolidin-3-yl)-1H-imidazole-5-carboxylate (170 mg). (Step 2) In addition to using the methyl (R)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl obtained in the above step 1 )-4-chloro-1-(1-isopropylpyrrolidin-3-yl)-1H-imidazole-5-carboxylate (170 mg) replaced the methyl group (R) used in Example 113 (step 2) -2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(1-(2,2-di The title compound (36 mg) was obtained by carrying out the same method as in Example 113 (step 2) except for fluoroethyl)pyrrolidin-3-yl)-1H-imidazole-5-carboxylate.

Example 115 (S)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-1H-imidazole-5-methamide In addition to using methyl (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-1H-imidazole-5-carboxylate obtained in Production Example 24, Except for methyl (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-1H-imidazole-5-carboxylate used in Production Example 25, the rest were used The title compound (24 mg) was obtained in the same manner as in Production Example 25, Production Example 51, and Example 113 (steps 1 and 2).

Example 116 (S)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(1-isopropylpyrrolidin-3-yl)-1H-imidazole-5-methamide In addition to using methyl (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-1H-imidazole-5-carboxylate obtained in Production Example 24, Except for methyl (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-1H-imidazole-5-carboxylate used in Production Example 25, the rest were used The title compound (12.1 mg) was obtained in the same manner as in Production Example 25, Production Example 51, and Example 114 (steps 1 and 2).

Example 117 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(1-(2,2-difluoroethyl)piperidin-3-yl)-1H-imidazole-5-methamide (Step 1) The same procedure as in Example 97 (Step 1) was carried out except that 1-Boc-3-hydroxypiperidine was used instead of (R)-(-)-3-hydroxytetrahydrofuran used in Example 97 (Step 1). -4) The same method, whereby tert-butyl 3-(5-((1-acrylyl azedine-3-yl)aminomethyl)-2-(((5-(tert- Butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1H-imidazol-1-yl)piperidine-1-carboxylate (40.2 mg). (Step 2) To tert-butyl 3-(5-((1-acrylyl azedine-3-yl)aminomethyl)-2-(((5-(tert -Butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1H-imidazol-1-yl)piperidine-1-carboxylate (40.2 mg) Acetic anhydride (0.5 mL) was added to the pyridine (0.5 mL) solution. After stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to column chromatography purification (chloroform:methanol). The purified product was concentrated, trifluoroacetic acid (0.5 mL) was added, and the reaction solution was concentrated to obtain 2-(((1-acetyl-5-(tert-butyl)-6-chloro-1H-indazole- 3-yl)amino)methyl)-N-(1-propenyl azedine-3-yl)-4-chloro-1-(piperidin-3-yl)-1H-imidazole-5-methyl Amide trifluoroacetate (43 mg. (Step 3) For 2-(((1-acetyl-5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) obtained in the above step 2 -N-(1-propenyl azedine-3-yl)-4-chloro-1-(piperidin-3-yl)-1H-imidazole-5-formamide trifluoroacetate (22 mg) To the methanol (0.2 mL) solution, add potassium acetate (10 mg), difluoroacetaldehyde hemiethyl acetate (30 μL), and 0.3 M sodium cyanoborohydride-1/2 zinc chloride in methanol solution (1.0 mL), and incubate at 40°C. Stir for 3 days. Water and ethyl acetate were added to the reaction liquid. The organic layer was separated, washed with 0.5N sodium hydroxide aqueous solution and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform:methanol) to obtain the title compound (3.0 mg).

Example 118 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-(1-methylpiperidin-3-yl)-1H-imidazole-5-methamide Instead of using 2-(((1-acetyl-5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl obtained in Example 117 (step 2) )-N-(1-propenyl azedine-3-yl)-4-chloro-1-(piperidin-3-yl)-1H-imidazole-5-formamide trifluoroacetate (20 mg) Substituting N-(1-acrylyl azetidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole) used in Example 91 (Step 9) Except for -3-yl)amino)methyl)-4-(difluoromethyl)-1-(pyrrolidin-3-yl)-1H-imidazole-5-carboxamide formate, the rest were processed with The same method as in Example 91 (step 9) was used to obtain the title compound (8.05 mg).

Example 119 (R)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(1-(2-methoxyethyl)pyrrolidin-3-yl)-1H-imidazole-5-methamide (Step 1) For Production Example 51, methyl(R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-(((5-(tert-butyl)-6 -Chloro-1H-indazole-3-yl)amino)methyl)-4-chloro-1H-imidazole-5-carboxylate (2.95g) was added trifluoroacetic acid (7.00mL) and incubated at room temperature After stirring for 15 minutes, concentrate. Toluene was added to the obtained residue, and concentration was repeated twice to obtain methyl (R)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl (3.76 g)-4-chloro-1-(pyrrolidin-3-yl)-1H-imidazole-5-carboxylate trifluoroacetic acid adduct. (Step 2) Stir 1,1,2-trimethoxyethane (2.5 mL), water (1.94 mL), and trifluoroacetic acid (1.94 mL) at 50°C for 25 minutes. The reaction solution was cooled to room temperature, and methyl (R)-2-(((5-(tert-butyl)) obtained in step 1 above was added to a solution of ethanol (9 mL) and triethylamine (3.53 mL). )-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(pyrrolidin-3-yl)-1H-imidazole-5-carboxylate trifluoroacetic acid addition The product (3.76g) was dissolved in ethanol (31mL). Sodium triacetoxyborohydride (6.88g) was added little by little and stirred at room temperature for 1 hour. 1N hydrochloric acid was added to the reaction solution, ethanol was concentrated, and ethyl acetate and 1N sodium hydroxide aqueous solution were added. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:ethanol), thereby obtaining methyl (R)-2-(((5-(tert-butyl) )-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(1-(2-methoxyethyl)pyrrolidin-3-yl)-1H- Imidazole-5-carboxylate (1.07g). (Step 3) In addition to using the methyl (R)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl obtained in the above step 2 )-4-chloro-1-(1-(2-methoxyethyl)pyrrolidin-3-yl)-1H-imidazole-5-carboxylate (1.07g) substituted in Example 113 (step 2) Methyl(R)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(1 Except for -(2,2-difluoroethyl)pyrrolidin-3-yl)-1H-imidazole-5-carboxylate, the same method as in Example 113 (step 2) was carried out to obtain the title compound. (540mg).

Example 120 (R)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(1-cyclopropylpyrrolidin-3-yl)-1H-imidazole-5-methamide (Step 1) Methyl (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-1H-imidazole-5-carboxylic acid obtained in Production Example 23 Trifluoroacetic acid (500 μL) was added to the ester (165 mg) and stirred at room temperature for 15 minutes. The reaction solution was concentrated, and methanol (3.0 mL), (1-ethoxycyclopropoxy)trimethylsilane (150 μL), acetic acid (200 μL), potassium acetate (100 mg), and sodium cyanoborohydride (200 mg) were added. and stir overnight at 50°C. The reaction solution was concentrated, and saturated aqueous sodium bicarbonate solution and ethyl acetate were added. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography purification (alkaline silica gel, hexane: ethyl acetate), thereby obtaining methyl (R)-4-chloro-1-(1-(cyclopropylpyrrolidine-3) -1H-imidazole-5-carboxylate (130 mg). (Step 2) In addition to the methyl (R)-4-chloro-1-(1-(cyclopropylpyrrolidin-3-yl)-1H-imidazole-5-carboxylate ( 130 mg) was substituted for the methyl (S)-4-chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-carboxylate used in Example 97 (step 2), and the rest was carried out as in Example 97 (step 2-4), thereby obtaining the title compound (94.3 mg).

Example 121 (R)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(1-(oxo-3-yl)pyrrolidin-3-yl)-1H-imidazole-5-methamide The same method as in Example 113 (steps 1, 2) was carried out except that oxybenza-3-one (11.5 mg) was used to replace the difluoroacetaldehyde hemiethyl acetate used in Example 113 (step 1). This gave the title compound (29.4 mg).

Example 122 (R)-N-(1-propenyl azedine-3-yl)-1-(1-benzylpyrrolidin-3-yl)-2-(((5-(tert-butyl)- 6-Chloro-1H-indazole-3-yl)amino)methyl)-4-chloro-1H-imidazole-5-carboxamide (Step 1) Methyl (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-2-methanoyl-1H- obtained in Production Example 25 Trifluoroacetic acid (3.0 mL) was added to imidazole-5-carboxylate (90 mg), and the mixture was stirred at room temperature for 5 minutes, and then the reaction solution was concentrated. Benzyl bromide (33 μL), DMF (1.0 mL), and sodium bicarbonate (70 mg) were added to the obtained residue, and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction liquid, and the organic layer was separated. Wash with saturated brine and dry with sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (chloroform: ethyl acetate), thereby obtaining methyl (R)-1-(1-benzylpyrrolidine-3- (28.3 mg)-4-chloro-2-formyl-1H-imidazole-5-carboxylate. (Step 2) In addition to using methyl (R)-1-(1-benzylpyrrolidin-3-yl)-4-chloro-2-formyl-1H-imidazole-5-carboxylic acid obtained in step 1 above The acid ester (28.3 mg) replaced the methyl (S)-4-chloro-2-methanoyl-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-carboxylic acid used in Example 97 (step 3). Except for the acid ester, the same method as in Example 97 (steps 3 and 4) was carried out to obtain the title compound (9.4 mg).

Example 123 (R)-N-(1-propenyl azedine-3-yl)-1-(1-allylpyrrolidin-3-yl)-2-((5-(tert-butyl) -6-Chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1H-imidazole-5-carboxamide The title compound (135 mg) was obtained in the same manner as in Example 122 (steps 1, 2) except that propylene bromide was used instead of benzyl bromide used in Example 122 (step 1).

Example 124 (R)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )methyl)-4-chloro-1-(1-(pyridin-2-yl)pyrrolidin-3-yl)-1H-imidazole-5-methamide (Step 1) Methyl (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-1H-imidazole-5-carboxylic acid obtained in Production Example 23 Trifluoroacetic acid (0.5 mL) was added to the ester (104 mg), and after stirring at room temperature for 5 minutes, the reaction solution was concentrated. Sodium bicarbonate (40 mg) and 2-fluoropyridine (1.0 mL) were added, and the mixture was reacted at 130° C. for 8 hours using a microwave reaction device. The reaction solution was purified by column chromatography (ethyl acetate:ethanol), thereby obtaining methyl (R)-4-chloro-1-(1-(pyridin-2-yl)pyrrolidin-3-yl) -1H-imidazole-5-carboxylate (112 mg). (Step 2) In addition to using methyl(R)-4-chloro-1-(1-(pyridin-2-yl)pyrrolidin-3-yl)-1H-imidazole-5-carboxylic acid obtained in step 1 above The ester (112 mg) was substituted for the methyl (S)-4-chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-carboxylate used in Example 97 (step 2), and the rest were carried out with The same method as Example 97 (Step 2-4) was used to obtain the title compound (57.9 mg).

Example 125 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-((2S,3R)-1-(2,2-difluoroethyl)-2-methylpyrrolidin-3-yl)-1H-imidazole-5-carboxamide (Step 1) The methanol used in Production Example 13 (Step 1) was replaced with tert-butyl(2S,3S)-3-hydroxy-2-methyl-pyrrolidine-1-carboxylate. Methyl 1-((2S,3R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidin-3-yl)-4 was obtained in the same manner as in Production Example 13 (Step 1). -Chloro-1H-imidazole-5-carboxylate (249 mg). (Step 2) To methyl 1-((2S,3R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidin-3-yl)-4-chloro-1H obtained in the above step 1 -Trifluoroacetic acid (1.5 mL) was added to a solution of imidazole-5-carboxylate (248 mg) in chloroform (3.0 mL), and the reaction solution was stirred at room temperature for 50 minutes, and then the reaction solution was concentrated. Heptane was added to the obtained residue, and the concentration under reduced pressure was repeated twice. Potassium acetate (106 mg), difluoroacetaldehyde hemiethyl alcohol (111 μL), and a methanol solution of 0.3 M sodium cyanoborohydride-1/2 zinc chloride (4.33 mL) were added to the obtained residue, and the mixture was stirred at room temperature. all night. Water, a saturated sodium bicarbonate aqueous solution, and ethyl acetate were added to the reaction solution, and the insoluble matter was filtered off, and then the organic layer was separated. Wash with saturated brine and dry with sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (hexane: ethyl acetate), thereby obtaining methyl 4-chloro-1-((2S,3R)-1- (2,2-Difluoroethyl)-2-methylpyrrolidin-3-yl)-1H-imidazole-5-carboxylate (183 mg). (Step 3) In addition to using the methyl 4-chloro-1-((2S,3R)-1-(2,2-difluoroethyl)-2-methylpyrrolidin-3-yl obtained in the above step 2) )-1H-imidazole-5-carboxylate (183 mg) substituted for methyl (S)-4-chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5 used in Example 97 (step 2) - Except for the carboxylic acid ester, the same method as in Example 97 (step 2-4) was carried out, whereby the title compound (108 mg) was obtained.

Example 126 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -4-Chloro-1-((3R,5R)-1-(2,2-difluoroethyl)-5-methylpyrrolidin-3-yl)-1H-imidazole-5-carboxamide In addition to using tert-butyl (2R,4S)-4-hydroxy-2-methyl-pyrrolidine-1-carboxylate (501 mg) instead of tert-butyl (2S) used in Example 125 (step 1), The title compound (71.8 mg) was obtained by carrying out the same method as Example 125 (step 1-3) except for 3S)-3-hydroxy-2-methyl-pyrrolidine-1-carboxylate.

Reference example 1 N-(1-propenyl azedine-3-yl)-2-(((5-bromo-6-chloro-1H-indazol-3-yl)amino)methyl)-1-methyl -1H-imidazole-5-methamide Except that 5-(tert-butyl)-6-chloro-1H- used in Example 1 was replaced with 5-bromo-6-chloro-1H-indazol-3-amine obtained in Production Example 5 (Step 1). The title compound (4.9 mg) was obtained by carrying out the same method as in Example 1 except for indazol-3-amine.

Reference example 2 N-(1-propenyl azedine-3-yl)-5-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) Furan-2-methamide (Step 1) For 5-methylfuran-2-carboxylic acid (223 mg), 1-(3-aminoazetidin-1-yl)prop-2-en-1-one trifluoromethanesulfonate ( 400 mg) in DMF (4 mL), add 1-hydroxybenzotriazole hydrate (333 mg), N,N-diisopropylethylamine (1.00 mL), and WSC hydrochloride (416 mg). After stirring at room temperature overnight, water and ethyl acetate were added. The organic layer was separated and washed with saturated brine. Dry with sodium sulfate, remove the solvent by distillation under reduced pressure, and subject the obtained residue to column chromatography purification (chloroform:methanol) to obtain N-(1-acrylyl azetidine-3-yl). )-5-methanofuran-2-methamide (235 mg). (Step 2) In addition to using N-(1-acrylyl azetidin-3-yl)-5-methanofuran-2-methamide obtained in the above step 1 to replace the N-( used in Example 1 Except for 1-acrylyl azedine-3-yl)-2-formyl-1-methyl-1H-imidazole-5-formamide, the same method as in Example 1 was carried out to obtain Title compound (26.6 mg).

Reference example 3 N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl) -1-Methyl-4-phenyl-1H-imidazole-5-methamide In addition to using tert-butyl 3-(2-formyl-1-methyl-4-phenyl-1H-imidazole-5-formamide)azetidine-1-carboxylate obtained in Production Example 39 (84 mg) substituted for tert-butyl 3-(2-formyl-4-methylthiazole-5-formamide)azetidine-1-carboxylate used in Example 2 (step 4) , and the same method as in Example 2 (steps 4, 5) was carried out to obtain the title compound (66.0 mg). Hereinafter, the compounds of Examples 1-126 and Reference Examples 1-3 are listed below.

[table 3]

[Table 4]

[table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Table 15]

[Table 16]

[Table 17]

Test Example 1 Binding test of compounds to KRASG12C The test compound was a DMSO solution prepared at 10mM. The proteins of K-Ras4B (1-169) and G12C K-Ras4B (1-169) were mixed and diluted with buffer (1×TBS, 0.1mM TCEP) to prepare 1 μM protein solutions respectively. The 10mM test compound was diluted 10 times with DMSO to make a 1mM solution, and then diluted 5 times with DMSO to make a 200μM solution. The 200 μM solution was further diluted 5 times to make a 40 μM solution. At a final compound concentration of 10 μM, 1 μL of 200 μM test compound was added to 19 μL of 1 μM protein solution. At a final compound concentration of 2 μM, 1 μL of 40 μM test compound was added to 19 μL of 1 μM protein solution. The mixture was stored in an incubator at 25° C. for 2 hours, and 80 μL of a 1×TBS solution containing 0.2% formic acid was added to stop the reaction, followed by LC-MS measurement. The LC-MS measurement uses Xevo G2-S Q-Tof manufactured by Waters Company, uses a desalting column for reverse-phase chromatography analysis, and uses electrospray to obtain a mass spectrum of positive ions. Mass spectrometry uses OpenLynx software and converts the spectrum of multivalent ions into molecular weights once using the MaxEnt method. The compound binding rate is obtained from the ratio of the signal intensity equivalent to the molecular weight of the protein to the signal intensity equivalent to the molecular weight of the compound bound to the protein. By simultaneously obtaining the binding rates of compounds to K-Ras4B (1-169) and G12C K-Ras4B (1-169), information on the selectivity to G12C K-Ras4B (1-169) can also be obtained at the same time. In the following, the test compound is measured at a final compound concentration of 2 μM. When the G12C K-Ras4B (1-169) binding rate is more than 80%, it is expressed as "A", and when the binding rate is more than 60% and less than 80%, it is expressed as " B", when the binding rate is more than 40% and less than 60%, it is marked as "C", when the bonding rate is more than 20% and less than 40%, it is marked as "D", when the bonding rate is less than 20%, it is marked as "E", and shown in the table below. In addition, almost no binding of the compounds of the present invention to K-Ras4B (1-169) was observed. Furthermore, the so-called binding rate (%) is the signal intensity of the compound conjugate on K-Ras4B (1-169) and G12C K-Ras4B (1-169) respectively, compared with the signal intensity of the non-conjugate and compound conjugate. Total ratio. " From this test result, it was found that the compound of the present invention has excellent binding ability to the K-Ras4B G12C mutant protein.

[Table 18]

Test Example 2 Evaluation of the inhibitory effect of compounds on the nucleotide (GDP-GTP) exchange reaction of KRAS G12C Human recombinant KRAS G12C and SOS1 proteins were used, and fluorescence measurement was used to explore the inhibitory effect of compounds on the following reactions, namely : The reaction of BODIPY (registered trademark) FL GDP bound to KRAS G12C is exchanged into GppNHp. When preparing KRAS G12C combined with BODIPY FL GDP, first, mix 50 μM KRAS G12C (amino acid region 1-169) and 1 mM BODIPY FL GDP (Invitrogen, G22360) in the presence of 2.5 mM EDTA in a buffer. solution (20mM Tris-HCl (pH7.5), 50mM NaCl, 1mM DTT) and incubate on ice for 1 hour. Afterwards, MgCl ₂ at a final concentration of 10 mM was added, and after incubation at room temperature for 30 minutes, the protein was passed through a NAP-5 column to remove free nucleotides and used for compound evaluation. When measuring the inhibitory activity of a compound on nucleotide exchange reaction, first, the compound of the present invention is diluted in stages with dimethylsulfoxide (DMSO). Next, a DMSO solution of the compound of the present invention that has been diluted stepwise in the reaction buffer (20mM Tris-HCl (pH7.5), 100mM NaCl, 1mM MgCl2, 2mM DTT, 0.1% Tween20) (the final concentration of DMSO is 5% ) and KRAS G12C (25nM) combined with BODIPY FL GDP, pre-cultured at 25°C for 4 hours. Thereafter, Son of Sevenless Homolog 1 (SOS1, amino acid region 564-1049) and GppNHp (GMPPNP, Jena Bioscience GmbH, NU-401-50) were added at final concentrations of 100 nM and 1 μM respectively, and allowed to react for 30 minutes. After normalizing the changes in BODIPY FL fluorescence intensity (excitation wavelength 485nm, fluorescence wavelength 520nm) immediately after the reaction started and 30 minutes later, the signal value with only DMSO was 0% hindrance, and the signal value without adding GppNHp was For 100% inhibition, the concentration of the compound that can inhibit 50% is calculated as the IC50 value (nM). Below, the inhibitory effect IC50 (nM) value of the tested compound is shown in the table below. From this test result, it was found that the compound of the present invention has excellent ability to inhibit the activity of the KRAS G12C mutant protein.

[Table 19]

Test Example 3 Proliferation inhibitory activity measurement test on KRAS-G12C mutant cell line (NCI-H358) (in vitro) NCI-H358 cells of the KRAS-G12C mutant human lung cancer cell line (ATCC, Cat#: CRL-5807) were suspended in RPMI1640 medium (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) containing 10% fetal calf serum. The cell suspension was seeded into each well of a 384-well flat-bottom microplate and cultured at 37°C for 1 day in an incubator containing 5% carbon dioxide gas. Dissolve the test compound in DMSO, and use DMSO to dilute the concentration of the test compound to 500 times the final concentration. The DMSO solution of the test compound was diluted with the culture medium used for cell suspension, and added so that the final concentration of DMSO in each well of the cell culture plate became 0.2%, in an incubator containing 5% carbon dioxide gas and Incubate further at 37°C for 3 days. The cell count test after 3 days of culture in the presence of the compound was performed using CellTiter-Glo 2.0 (manufactured by Promega) and in accordance with the procedures recommended by Promega. Calculate the proliferation inhibition rate using the following formula, and determine the concentration of the test compound that inhibits 50% (IC50 (nM)). The results are shown in the table below. Proliferation inhibition rate (%) = (C-T)/(C)×100 T: Luminous intensity of the well where the test compound is added C: Luminous intensity of wells without test compound added From the test results, it was learned that the compound of the present invention has excellent cell proliferation inhibitory activity on the KRAS-G12C mutant cell line NCI-H358.

[Table 20]

Claims (31)

An indazole compound or a salt thereof is represented by the following general formula (I):

_[ In the formula _, The C2-C6 alkenyl group of the substituent or the C3-C10 cycloalkyl group which may also have a substituent; L ₁ represents -NH-C(Ra) ₂ -, (in the formula, Ra is the same or different and represents a hydrogen atom, deuterium atom or C1-C6 alkyl); ring A represents a 5-membered unsaturated heterocyclic group that may also have a substituent; one of A1, A2 and A3 is a nitrogen atom or a sulfur atom that may also have a substituent, and The remaining A1, A2 and A3 are the same or different, indicating a carbon atom that may have a substituent, a nitrogen atom, a sulfur atom or an oxygen atom that may have a substituent; A1 is a carbon atom with a substituent or a substituent. When a nitrogen atom is used, the substituent represents: a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a C1-C6 alkyl group that may also have Rb, and a C2 group that may also have Rb. -C6 alkenyl, it may also have a C2-C6 alkynyl group with Rb, it may also have a C3-C10 cycloalkyl group with Rc, it may also have a C4-C10 cycloalkenyl group with Rc, it may also have a C6~C10 aromatic group with Rc At least one of the group consisting of a hydrocarbon group, a saturated heterocyclic group that may have 4 to 10 members of Rc, and an unsaturated heterocyclic group that may have 5 to 10 members of Rc, (Rb represents a halogen atom, a cyano group , nitro group, amino group, hydroxyl group, carboxyl group, C1-C6 alkoxy group, C1-C6 alkylamino group, C3-C6 cycloalkyl group, C6-C10 aromatic hydrocarbon group that may also have a substituent, or a C6-C10 aromatic hydrocarbon group that may also have a substituent A saturated heterocyclic group with 5 to 10 substituents, Rc represents a halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1 -C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkylcarbonyl, C1-C6 alkoxy -C1-C6 alkyl, C7-C20 aralkyl, C1- C6 alkoxycarbonyl, C3-C6 cycloalkyl, C6-C10 aromatic hydrocarbon group, 5 to 10-membered saturated heterocyclic group or 5 to 10-membered unsaturated heterocyclic group, when there are multiple Rb groups, the majority Each Rb can be the same or different, and when there are multiple Rcs, the multiple Rcs can be the same or different); when A2 is a carbon atom with a substituent or a nitrogen atom with a substituent, the substituent represents: Free: hydrogen atom, halogen atom, cyano group, nitro group, amino group, hydroxyl group, carboxyl group, C1-C6 alkyl group which may also have a substituent, C2-C6 alkenyl group which may also have a substituent, and At least one of the groups consisting of C2-C6 alkynyl groups of substituents; when A3 is a carbon atom with a substituent or a nitrogen atom with a substituent, the substituent represents: selected from the group consisting of hydrogen atom, halogen atom, cyanide atom A group consisting of a nitro group, an amino group, a hydroxyl group, a carboxyl group, a C1-C6 alkyl group that may have a substituent, a C2-C6 alkenyl group that may have a substituent, and a C2-C6 alkynyl group that may have a substituent. At least one of the group; L ₂ means:

(In the formula,

Represents a 4 to 8-membered saturated heterocyclic group with at least 1 nitrogen atom, in which N represents a nitrogen atom, and may also have 1 or 2 heteroatoms selected from sulfur atoms and oxygen atoms, and R ₃ represents a hydrogen atom or C1-C6 alkyl group, R ₄ represents halogen atom, cyano group, nitro group, amine group, hydroxyl group, carboxyl group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C1-C6 haloalkyl, C1-C6 alkylamino-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl or C1-C6 hydroxyalkyl, When there are multiple R _4s , the multiple R _4s may be the same or different. When the same carbon atom is replaced by two R _4s and the two R _4s are C1-C6 alkyl groups, the two R _4s may be Together with the carbon atoms to which these groups are bonded, they form a ring, n represents 0, 1, 2 or 3); L ₃ represents -C(=O)- or -S(=O) ₂ -; R ₅ represents also A C2-C6 alkenyl group having a substituent or a C2-C6 alkynyl group which may also have a substituent]. For example, the compound of claim 1 or a salt thereof, wherein two of A1, A2 and A3 are the same or different, and are nitrogen atoms or sulfur atoms that may have substituents, and the rest are carbon atoms that may also have substituents. Such as the compound of claim 1 or 2 or a salt thereof, wherein A1 is a carbon atom with a substituent or a nitrogen atom with a substituent, and the substituent is: selected from a hydrogen atom, a halogen atom, and may also have Rb C1-C6 alkyl group, C2-C6 alkenyl group with Rb, C3-C10 cycloalkyl group with Rc, C4-C10 cycloalkenyl group with Rc, or 5 to 10 members of Rc At least one of the group consisting of a saturated heterocyclic group and an unsaturated heterocyclic group that may also have 5 to 10 members of Rc (Rb and Rc are the same as above). The compound of claim 1 or 2 or a salt thereof, wherein the substituent of A3 is at least one selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a C1-C6 alkyl group and a C1-C6 haloalkyl group. One kind. Such as the compound of claim 1 or 2 or its salt, wherein L ₂ is

(In the formula,

It is a saturated heterocyclic group with 1 or 2 nitrogen atoms as 4 to 6 members of the heteroatom, where N represents a nitrogen atom, and R ₃ is a hydrogen atom or a methyl group, and R ₄ is a halogen atom, cyano group, hydroxyl, C1 -C3 alkyl, methoxy, C1-C3 haloalkyl, dimethylaminomethyl or ethoxymethyl, and when there are multiple R _4s , the multiple R _4s may be the same or different, n is 0, 1 or 2). For example, the compound of claim 1 or 2 or its salt, wherein L ₃ is -C(=O)-. The compound of claim 1 or 2 or a salt thereof, wherein R ₅ is vinyl or 1-propynyl. The compound of claim 1 or 2 or a salt thereof, wherein R ₅ is vinyl. Such as the compound of claim 1 or 2 or its salt, wherein X is CH. The compound of claim 1 or 2 or a salt thereof, wherein L ₁ is -NH-CH ₂ -. Such as the compound of claim 1 or 2 or its salt, wherein R ₁ is a chlorine atom. The compound of claim 1 or 2 or a salt thereof, wherein R ₂ is a C1-C6 alkyl group. The compound of claim 1 or 2 or a salt thereof, wherein R ₂ is tert-butyl. For example, the compound of claim 1 or 2 or a salt thereof, wherein A1 is a nitrogen atom that may have a substituent, A2 is a nitrogen atom that may have a substituent, and A3 is a carbon atom that may also have a substituent. Such as the compound of claim 1 or 2 or its salt, wherein L ₂ is

(In the formula,

It is a saturated heterocyclic group with 4 to 5 members containing 1 nitrogen atom as a heteroatom, where N represents a nitrogen atom, R ₃ represents a hydrogen atom, R ₄ is a halogen atom, C1-C2 alkyl group or methoxy group, R ₄ When there are a plurality of R 4's, the plurality of R ₄ 's may be the same or different, and n is 0, 1 or 2). For example, the compound of claim 1 or 2 or its salt, wherein the compound is selected from the following compound group: ‧N-(1-acrylyl azedine-3-yl)-2-(((5-(tert- Butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-methyl Amide; ‧N-(1-propenyl azetidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amine) )Methyl)-1-isopropyl-4-methyl-1H-imidazole-5-methamide; ‧N-(1-propenyl azedine-3-yl)-2-(((5 -(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-methyl-1H-imidazole-5-carboxamide; ‧N- (1-Acrylyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4 -(Difluoromethyl)-1-isopropyl-1H-imidazole-5-methamide; ‧N-(1-propenyl azedine-3-yl)-2-(((5-( tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-isopropyl-1H-imidazole-5-methamide; ‧N-( (3S,4S)-1-Acrylyl-4-fluoropyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl) Amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide; ‧N-((3S,4S)-1-acrylyl-4-fluoropyrrolidin-3-yl )-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-fluoro-1-methyl-1H-imidazole-5 -Formamide; ‧N-((3S,4S)-1-propenyl-4-fluoropyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro- 1H-indazol-3-yl)amino)methyl)-4-chloro-1-methyl-1H-imidazole-5-methamide; ‧N-((3R,4R)-1-acrylamide -4-methylpyrrolidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methane base)-4-chloro-1-methyl-1H-imidazole-5-methamide; ‧N-(1-acrylyl azedine-3-yl)-2-(((5-(tert- Butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1-(1-isopropylpyrrolidin-3-yl)-1H -imidazole-5-carboxamide; ‧(S)-N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H -indazol-3-yl)amino)methyl)-4-chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-carboxamide; ‧N-(1-propenyl azedine Din-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(tetrahydro -2H-pyran-4-yl)-1H-imidazole-5-methamide; ‧(R)-N-(1-propenyl azedine-3-yl)-2-(((5- (tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(tetrahydrofuran-3-yl)-1H-imidazole-5-methamide ;‧N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl base)-4-chloro-1-(1-methylpiperidin-4-yl)-1H-imidazole-5-methamide; ‧N-(1-propenyl azedine-3-yl)- 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(tetrahydro-2H-piran-3 -yl)-1H-imidazole-5-carboxamide; ‧N-(1-acrylyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro- 1H-indazol-3-yl)amino)methyl)-4-chloro-1-cyclopentyl-1H-imidazole-5-methamide; ‧tert-butyl 3-(5-((1- Acrylyl azetidin-3-yl)aminomethyl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methane base)-4-chloro-1H-imidazol-1-yl)acetidine-1-carboxylate; ‧N-(1-propenyl azedine-3-yl)-2-(((5- (tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(1-isopropylazetidine-3-yl)-1H- Imidazole-5-carboxamide; ‧N-(1-propenyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazole-3) -(yl)amino)methyl)-4-chloro-1-(4-methoxycyclohexyl)-1H-imidazole-5-methamide; ‧(R)-N-(1-acrylamide) Butidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(1 -(2,2-Difluoroethyl)pyrrolidin-3-yl)-1H-imidazole-5-carboxamide; ‧(R)-N-(1-propenyl azedine-3-yl) -2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(1-isopropylpyrrolidine- 3-yl)-1H-imidazole-5-carboxamide; ‧(S)-N-(1-propenyl azedine-3-yl)-2-((5-(tert-butyl) -6-Chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-(1-(2,2-difluoroethyl)pyrrolidin-3-yl)-1H- Imidazole-5-carboxamide; ‧(R)-N-(1-propenyl azedine-3-yl)-1-(1-allylpyrrolidin-3-yl)-2-(( (5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1H-imidazole-5-carboxamide; ‧(R)-N -(1-Acrylyl azedine-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)- 4-Chloro-1-(1-(pyridin-2-yl)pyrrolidin-3-yl)-1H-imidazole-5-methamide; and ‧N-(1-propenyl azedine-3- base)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-((3R,5R)- 1-(2,2- Difluoroethyl)-5-methylpyrrolidin-3-yl)-1H-imidazole-5-carboxamide. A medicine containing a compound according to any one of claims 1 to 16 or a salt thereof. A pharmaceutical composition containing a compound according to any one of claims 1 to 16 or a salt thereof and a pharmaceutically acceptable carrier. An anti-tumor agent containing the compound according to any one of claims 1 to 16 or a salt thereof as an active ingredient. An anti-tumor agent for oral administration, which contains the compound according to any one of claims 1 to 16 or a salt thereof as an active ingredient. The use of a compound or a salt thereof according to any one of claims 1 to 16 is used to produce an anti-tumor agent. Use of a compound or a salt thereof according to any one of claims 1 to 16, for the manufacture of an anti-tumor agent for oral administration. A commercial kit simultaneously containing as an active ingredient a compound or a salt thereof according to any one of claims 1 to 16 and instructions for using the compound or a salt thereof in treating tumors of a subject. For example, the compound of claim 1 or 2 or its salt is used as a medicine. For example, the compound of claim 1 or 2 or its salt is used for treating tumors. For example, the compound of claim 1 or 2 or its salt is used for oral administration to treat tumors. An anti-tumor agent, which contains a compound or a salt thereof according to any one of claims 1 to 16 and one or more other anti-tumor agents as an active ingredient active ingredients. An anti-tumor agent using a compound or a salt thereof according to any one of claims 1 to 16 as an active ingredient, characterized in that it is administered in combination with one or more other anti-tumor agents. The use of a compound or salt thereof according to any one of claims 1 to 16 and one or more other anti-tumor agents is used to produce an anti-tumor agent. A compound or a salt thereof according to any one of claims 1 to 16 for treating tumors, characterized in that it is administered in combination with one or more other anti-tumor agents. A combination of a compound or a salt thereof according to any one of claims 1 to 16 and one or more other anti-tumor agents is used to treat tumors.